5-anilinoimidazopyridines and methods of use

ABSTRACT

The invention relates to a method of inhibiting abnormal cell growth or treating a hyperproliferative disorder in a mammal comprising administering to said mammal a therapeutically effective amount of an imidazopyridine of formula I with anti-hyperproliferative activity.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. Ser. No. 13/586,147, filedAug. 15, 2012 which is a continuation of U.S. Ser. No. 13/041,735, filedMar. 7, 2011 which is a divisional application of U.S. Pat. No.7,923,456, issued Apr. 12, 2011, which claims the benefit of priority tointernational application number PCT/US2008/087482 and to U.S.provisional Application Ser. No. 61/015,129, filed 19 Dec. 2007, and toU.S. provisional Application Ser. No. 61/054,014, filed 16 May 2008, thedisclosures of all are incorporated herein by reference in theirentirety.

FIELD OF THE INVENTION

The invention relates to imidazopyridines with anti-cancer activity andmore specifically to imidazopyridines which inhibit MEK kinase activity.The invention also relates to methods of using the compounds for invitro, in situ, and in vivo diagnosis or treatment of mammalian cells,or associated pathological conditions.

BACKGROUND OF THE INVENTION

In the quest to understand how Ras transmits extracellular growthsignals, the MAP (mitogen-activated protein) kinase (MAPK) pathway hasemerged as the crucial route between membrane-bound Ras and the nucleus.The MAPK pathway encompasses a cascade of phosphorylation eventsinvolving three key kinases, namely Raf, MEK (MAP kinase kinase) and ERK(MAP kinase). Active GTP-bound Ras results in the activation andindirect phosphorylation of Raf kinase. Raf then phosphorylates MEK1 and2 on two serine residues (S218 and 5222 for MEK1 and S222 and 5226 forMEK2) (Ahn et al., Methods in Enzymology 2001, 332, 417-431). ActivatedMEK then phosphorylates its only known substrates, the MAP kinases, ERK1and 2. ERK phosphorylation by MEK occurs on Y204 and T202 for ERK1 andY185 and T183 for ERK2 (Ahn et al., Methods in Enzymology 2001, 332,417-431). Phosphorylated ERK dimerizes and then translocates to thenucleus where it accumulates (Khokhlatchev et al., Cell 1998, 93,605-615). In the nucleus, ERK is involved in several important cellularfunctions, including but not limited to nuclear transport, signaltransduction, DNA repair, nucleosome assembly and translocation, andmRNA processing and translation (Ahn et al., Molecular Cell 2000, 6,1343-1354). Overall, treatment of cells with growth factors leads to theactivation of ERK1 and 2 which results in proliferation and, in somecases, differentiation (Lewis et al., Adv. Cancer Res. 1998, 74,49-139).

There has been strong evidence that genetic mutations and/oroverexpression of protein kinases involved in the MAP kinase pathwaylead to uncontrolled cell proliferation and, eventually, tumorformation, in proliferative diseases. For example, some cancers containmutations which result in the continuous activation of this pathway dueto continuous production of growth factors. Other mutations can lead todefects in the deactivation of the activated GTP-bound Ras complex,again resulting in activation of the MAP kinase pathway. Mutated,oncogenic forms of Ras are found in 50% of colon and >90% pancreaticcancers as well as many others types of cancers (Kohl et al., Science1993, 260, 1834-1837). Recently, bRaf mutations have been identified inmore than 60% of malignant melanoma (Davies, H. et al., Nature 2002,417, 949-954). These mutations in bRaf result in a constitutively activeMAP kinase cascade. Studies of primary tumor samples and cell lines havealso shown constitutive or overactivation of the MAP kinase pathway incancers of pancreas, colon, lung, ovary and kidney (Hoshino, R. et al.,Oncogene 1999, 18, 813-822).

MEK has emerged as an attractive therapeutic target in the MAP kinasecascade pathway. MEK, downstream of Ras and Raf, is highly specific forthe phosphorylation of MAP kinase; in fact, the only known substratesfor MEK phosphorylation are the MAP kinases, ERK1 and 2. Inhibition ofMEK has been shown to have potential therapeutic benefit in severalstudies. For example, small molecule MEK inhibitors have been shown toinhibit human tumor growth in nude mouse xenografts, (Sebolt-Leopold etal., Nature-Medicine 1999, 5 (7), 810-816); Trachet et al., AACR Apr.6-10, 2002, Poster #5426; Tecle, H. IBC 2.sup.nd InternationalConference of Protein Kinases, Sep. 9-10, 2002), block static allodyniain animals (WO 01/05390 published Jan. 25, 2001) and inhibit growth ofacute myeloid leukemia cells (Milella et al., J Clin Invest 2001, 108(6), 851-859).

Several small molecule MEK inhibitors have also been discussed in, forexample, WO02/06213, WO 03/077855 and WO03/077914. There still exists aneed for new MEK inhibitors as effective and safe therapeutics fortreating a variety of proliferative disease states, such as conditionsrelated to the hyperactivity of MEK, as well as diseases modulated bythe MEK cascade.

SUMMARY OF THE INVENTION

The invention relates generally to imidazopyridines of formula I (and/orsolvates, hydrates and/or salts thereof) with anti-cancer and/oranti-inflammatory activity, and more specifically with MEK kinaseinhibitory activity. Certain hyperproliferative and inflammatorydisorders are characterized by the modulation of MEK kinase function,for example by mutations or overexpression of the proteins. Accordingly,the compounds of the invention and compositions thereof are useful inthe treatment of hyperproliferative disorders such as cancer and/orinflammatory diseases such as rheumatoid arthritis.

and salts thereof, wherein:

Z¹ is CR¹ or N;

R¹ is H, C₁-C₃ alkyl, halo, CF₃, CHF₂, CN, OR^(A) or NR^(A)R^(A);

R^(1′) is H, C₁-C₃ alkyl, halo, CF₃, CHF₂, CN, OR^(A), or NR^(A)R^(A);

wherein each R^(A) is independently H or C₁-C₃ alkyl;

Z² is CR² or N;

Z³ is CR³ or N; provided that only one of Z¹, Z² and Z³ can be N at thesame time;

R² and R³ are independently selected from H, halo, CN, CF₃, —OCF₃, —NO₂,—(CR¹⁴R¹⁵)_(n)C(═Y′)R¹¹, —(CR¹⁴R¹⁵)_(n)C(═Y′)OR¹¹,—(CR¹⁴R¹⁵)_(n)C(═Y′)NR¹¹R¹², —(CR¹⁴R¹⁵)_(n)NR¹¹R¹²,—(CR¹⁴R¹⁵)_(n)OR¹¹,—(CR¹⁴R¹⁵)_(n)SR¹¹, —(CR¹⁴R¹⁵)_(n)NR¹²C(═Y′)R¹¹,—(CR¹⁴R¹⁵)_(n)NR¹²C(═Y′)OR¹¹, —(CR¹⁴R¹⁵)_(n)NR¹³C(═Y′)NR¹¹R¹²,—(CR¹⁴R¹⁵)_(n)NR¹²SO₂R¹¹, —(CR¹⁴R¹⁵)_(n)OC(═Y′)R¹¹,—(CR¹⁴R¹⁵)_(n)OC(═Y′)OR¹¹, —(CR¹⁴R¹⁵)_(n)OC(═Y′)NR¹¹R¹²,—(CR¹⁴R¹⁵)_(n)OS(O)₂(OR¹¹), —(CR¹⁴R¹⁵)_(n)OP(═Y′) (OR¹¹)(OR¹²),—(CR¹⁴R¹⁵)_(n)OP(OR¹¹)(OR¹²), —(CR¹⁴R¹⁵)_(n)S(O)R¹¹,—(CR¹⁴R¹⁵)_(n)S(O)₂R¹¹, —(CR¹⁴R¹⁵)_(n)S(O)₂NR¹¹R¹²,—(CR¹⁴R¹⁵)_(n)S(O)(OR¹¹), —(CR¹⁴R¹⁵)_(n)S(O)₂(OR¹¹),—(CR¹⁴R¹⁵)_(n)SC(═Y′)R¹¹, —(CR¹⁴R¹⁵)_(n)SC(═Y′)OR¹¹,—(CR¹⁴R¹⁵)_(n)SC(═Y′)NR¹¹R¹², C₁-C₁₂ alkyl, C₂-C₈ alkenyl, C₂-C₈alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl;

R⁴ is H, C₁-C₆ alkyl or C₃-C₄ carbocyclyl;

Y is W—C(O)— or W′;

W is

R⁵ is H or C₁-C₁₂ alkyl;

X¹ is selected from R^(11′) and —OR^(11′); when X¹ is R^(11′), X¹ isoptionally taken together with R⁵ and the nitrogen atom to which theyare bound to form a 4-7 membered saturated or unsaturated ring having0-2 additional heteroatoms selected from O, S and N, wherein said ringis optionally substituted with one or more groups selected from halo,CN, CF₃, —OCF₃, —NO₂, oxo, —(CR¹⁹R²⁰)_(n)C(═Y′)R¹⁶,—(CR¹⁹R²⁰)_(n)C(═Y′)OR¹⁶, —(CR¹⁹R²⁰)_(n)C(═Y′)NR¹⁶R¹⁷,—(CR¹⁹R²⁰)_(n)NR¹⁶R¹⁷, —(CR¹⁹R²⁰)_(n)OR¹⁶, —(CR¹⁹R²⁰)_(n)—SR¹⁶,—(CR¹⁹R²⁰)_(n)NR¹⁶C(═Y)R¹⁷, —(CR¹⁹R²⁰)_(n)NR¹⁶C(═Y′)OR¹⁷,—(CR¹⁹R²⁰)_(n)NR¹⁸C(═Y′)NR¹⁶R¹⁷, —(CR¹⁹R²⁰)_(n)NR¹⁷SO₂R¹⁶,—(CR¹⁹R²⁰)_(n)OC(═Y′)R¹⁶, —(CR¹⁹R²⁰)_(n)OC(═Y′)OR¹⁶,—(CR¹⁹R²⁰)_(n)OC(═Y′)NR¹⁶R¹⁷, —(CR¹⁹R²⁰)_(n)OS(O)₂(OR¹⁶),—(CR¹⁹R²⁰)_(n)OP(═Y′)(OR¹⁶)(OR¹⁷), —(CR¹⁹R²⁰)_(n)OP(OR¹⁶)(OR¹⁷),—(CR¹⁹R²⁰)_(n)S(O)R¹⁶, —(CR¹⁹R²⁰)_(n)S(O)₂R¹⁶,—(CR¹⁹R²⁰)_(n)S(O)₂NR¹⁶R¹⁷, —(CR¹⁹R²⁰)_(n)S(O)(OR¹⁶),—(CR¹⁹R²⁰)_(n)S(O)₂(OR¹⁶), —(CR¹⁹R²⁰)_(n)SC(═Y′)R¹⁶, —(CR¹⁹R²⁰)_(n)SC(═Y′)OR¹⁶, —(CR¹⁹R²⁰)_(n)SC(═Y)NR¹⁶R¹⁷, and R²¹;

each R^(11′) is independently H, C₁-C₁₂ alkyl, C₂-C₈ alkenyl, C₂-C₈alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl;

R¹¹, R¹² and R¹³ are independently H, C₁-C₁₂ alkyl, C₂-C₈ alkenyl, C₂-C₈alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl,

or R¹¹ and R¹² together with the nitrogen to which they are attachedform a 3-8 membered saturated, unsaturated or aromatic ring having 0-2heteroatoms selected from O, S and N, wherein said ring is optionallysubstituted with one or more groups selected from halo, CN, CF₃, —OCF₃,—NO₂, C₁-C₆ alkyl, —OH, —SH, —O(C₁-C₆ alkyl), —S(C₁-C₆ alkyl), —NH₂,—NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —SO₂(C₁-C₆ alkyl), —CO₂H, —CO₂(C₁-C₆alkyl), —C(O)NH₂, —C(O)NH(C₁-C₆ alkyl), —C(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆alkyl)C(O)(C₁-C₆ alkyl), —NHC(O)(C₁-C₆ alkyl), —NHSO₂(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)SO₂(C₁-C₆ alkyl), —SO₂NH₂, —SO₂NH(C₁-C₆ alkyl),—SO₂N(C₁-C₆ alkyl)₂, —OC(O)NH₂, —OC(O)NH(C₁-C₆ alkyl), —OC(O)N(C₁-C₆alkyl)₂, —OC(O)O(C₁-C₆ alkyl), —NHC(O)NH(C₁-C₆ alkyl), —NHC(O)N(C₁-C₆alkyl)₂, —N(C₁-C₆ alkyl)C(O)NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)C(O)N(C₁-C₆alkyl)₂, —NHC(O)NH(C₁-C₆ alkyl), —NHC(O)N(C₁-C₆ alkyl)₂, —NHC(O)O(C₁-C₆alkyl), and —N(C₁-C₆ alkyl)C(O)O(C₁-C₆ alkyl);

R¹⁴ and R¹⁵ are independently selected from H, C₁-C₁₂ alkyl, aryl,carbocyclyl, heterocyclyl, and heteroaryl;

W′ is

wherein

each X² is independently O, S, or NR⁹;

each R⁷ is independently selected from H, halo, CN, CF₃, —OCF₃, —NO₂,—(CR¹⁴R¹⁵)_(n)C(═Y′)R¹¹, —(CR¹⁴R¹⁵)_(n)C(═Y′)OR¹¹,—(CR¹⁴R¹⁵)_(n)C(═Y′)NR¹¹R¹², —(CR¹⁴R¹⁵)_(n)NR¹¹R¹², —(CR¹⁴R¹⁵)_(n)OR¹¹,—(CR¹⁴R¹⁵)_(n)SR¹¹, —(CR¹⁴R¹⁵)_(n)NR¹²C(═Y′)R¹¹,—(CR¹⁴R¹⁵)_(n)NR¹²C(═Y′)OR¹¹, —(CR¹⁴R¹⁵)_(n)NR¹³C(═Y′)NR¹¹R¹²,—(CR¹⁴R¹⁵)_(n)NR¹²SO₂R¹¹, —(CR¹⁴R¹⁵)_(n)OC(═Y′)R¹¹,—(CR¹⁴R¹⁵)_(n)OC(═Y′)OR¹¹, —(CR¹⁴R¹⁵)_(n)OC(═Y′)NR¹¹R¹²,—(CR¹⁴R¹⁵)_(n)OS(O)₂(OR¹¹), —(CR¹⁴R¹⁵)_(n)OP(═Y′)(OR¹¹)(OR¹²),—(CR¹⁴R¹⁵)_(n)OP(OR¹¹)(OR¹²), —(CR¹⁴R¹⁵)_(n)S(O)R¹¹,—(CR¹⁴R¹⁵)_(n)S(O)₂R¹¹, —(CR¹⁴R¹⁵)_(n)S(O)₂NR¹¹R¹²,—(CR¹⁴R¹⁵)_(n)S(O)(OR¹¹), —(CR¹⁴R¹⁵)_(n)S(O)₂(OR¹¹),—(CR¹⁴R¹⁵)_(n)SC(═Y′)R¹¹, —(CR¹⁴R¹⁵)_(n)SC(═Y′)OR¹¹,—(CR¹⁴R¹⁵)_(n)SC(═Y′)NR¹¹R¹², C₁-C₁₂ alkyl, C₂-C₈ alkenyl, C₂-C₈alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl;

each R⁸ is independently selected from C₁-C₁₂ alkyl, aryl, carbocyclyl,heterocyclyl, and heteroaryl;

R⁹ is selected from H, —(CR¹⁴R¹⁵)_(n)C(═Y′)R¹¹,—(CR¹⁴R¹⁵)_(n)C(═Y′)OR¹¹, —(CR¹⁴R¹⁵)_(n)C(═Y′)NR¹¹R¹²,—(CR¹⁴R¹⁵)_(q)NR¹¹R¹², —(CR¹⁴R¹⁵)_(q)OR¹¹, —(CR¹⁴R¹⁵)_(q)SR¹¹,—(CR¹⁴R¹⁵)_(q)NR¹²C(═Y′)R¹¹, —(CR¹⁴R¹⁵)_(q)NR¹²C(═Y′)OR¹¹,—(CR¹⁴R¹⁵)_(q)NR¹³C(═Y′)NR¹¹R¹², —(CR¹⁴R¹⁵)_(q)NR¹²SO₂R¹¹,—(CR¹⁴R¹⁵)_(q)OC(═Y′)R¹¹, —(CR¹⁴R¹⁵)_(q)OC(═Y′)OR¹¹,—(CR¹⁴R¹⁵)_(q)OC(═Y′)NR¹¹R¹², —(CR¹⁴R¹⁵)_(q)OS(O)₂(OR¹¹),—(CR¹⁴R¹⁵)_(q)OP(═Y′)(OR¹¹)(OR¹²), —(CR¹⁴R¹⁵)_(q)OP(OR¹¹)(OR¹²),—(CR¹⁴R¹⁵)S(O)R¹¹, —(CR¹⁴R¹⁵)_(n)S(O)₂R¹¹, —(CR¹⁴R¹⁵)_(n)S(O)₂NR¹¹R¹²,C₁₋₂ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, carbocyclyl, heterocyclyl,aryl, and heteroaryl;

R¹⁰ is H, C₁-C₆ alkyl or C₃-C₄ carbocyclyl;

X⁴ is

R⁶ is H, halo, C₁-C₆ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, carbocyclyl,heteroaryl, heterocyclyl, —OCF₃, —NO₂, —Si(C₁-C₆ alkyl),—(CR¹⁹R²⁰)_(n)NR¹⁶R¹⁷, —(CR¹⁹R²⁰)_(n)OR¹⁶, or —(CR¹⁹R²⁰)_(n)—SR¹⁶;

R^(6′) is H, halo, C₁-C₆ alkyl, carbocyclyl, CF₃, —OCF₃, —NO₂, —Si(C₁-C₆alkyl), —(CR¹⁹R²⁰)_(n)NR¹⁶R¹⁷, —(CR¹⁹R²⁰)_(n)OR¹⁶, —(CR¹⁹R²⁰)_(n)—SR¹⁶,C₂-C₈ alkenyl, C₂-C₈ alkynyl, heterocyclyl, aryl, or heteroaryl;

p is 0, 1, 2 or 3;

n is 0, 1, 2 or 3;

q is 2 or 3;

wherein each said alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl,aryl and heteroaryl of R¹, R², R³, R⁴, R⁵, R⁶, R^(6′), R⁷, R⁸, R⁹, R¹⁰,R¹¹, R¹², R¹³, R¹⁴, R¹⁵ and R^(A) is independently optionallysubstituted with one or more groups independently selected from halo,CN, CF₃, —OCF₃, —NO₂, oxo, —Si(C₁-C₆ alkyl), —(CR¹⁹R²⁰)_(n)C(═Y′)R¹⁶,—(CR¹⁹R²⁰)_(n)C(═Y′)OR¹⁶, —(CR¹⁹R²⁰)_(n)C(═Y′)NR¹⁶R¹⁷,—(CR¹⁹R²⁰)_(n)NR¹⁶R¹⁷, —(CR¹⁹R²⁰)_(n)OR¹⁶, —(CR¹⁹R²⁰)_(n)SR¹⁶,—(CR¹⁹R²⁰)_(n)NR¹⁶C(═Y′)R¹⁷, —(CR¹⁹R²⁰)_(n)NR¹⁶C(═Y′)OR¹⁷,—(CR¹⁹R²⁰)_(n)NR¹⁸C(═Y′)NR¹⁶R¹⁷, —(CR¹⁹R²⁰)_(n)NR¹⁷SO₂R¹⁶,—(CR¹⁹R²⁰)_(n)OC(═Y′)R¹⁶, —(CR¹⁹R²⁰)_(n)OC(═Y′)OR¹⁶,—(CR¹⁹R²⁰)_(n)OC(═Y′)NR¹⁶R¹⁷, —(CR¹⁹R²⁰)_(n)OS(O)₂(OR¹⁶),—(CR¹⁹R²⁰)_(n)OP(═Y′)(OR¹⁶)(OR¹⁷), —(CR¹⁹R²⁰)_(n)OP(OR¹⁶)(OR¹⁷),—(CR¹⁹R²⁰)_(n)S(O)R¹⁶, —(CR¹⁹R²⁰)_(n)S(O)₂R¹⁶,—(CR¹⁹R²⁰)_(n)S(O)₂NR¹⁶R¹⁷, —(CR¹⁹R²⁰)_(n)S(O)(OR¹⁶),—(CR¹⁹R²⁰)_(n)S(O)₂(OR¹⁶), —(CR¹⁹R²⁰)_(n)SC(═Y′)R¹⁶,—(CR¹⁹R²⁰)_(n)SC(═Y′)OR¹⁶, —(CR¹⁹R²⁰)_(n)SC(═Y′)NR¹⁶R¹⁷, and R²¹;

each R¹⁶, R¹⁷ and R¹⁸ is independently H, C₁-C₁₂ alkyl, C₂-C₈ alkenyl,C₂-C₈ alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl, whereinsaid alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, orheteroaryl is optionally substituted with one or more groups selectedfrom halo, CN, —OCF₃, CF₃, —NO₂, C₁-C₆ alkyl, —OH, —SH, —O(C₁-C₆ alkyl),—S(C₁-C₆ alkyl), —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —SO₂(C₁-C₆alkyl), —CO₂H, —CO₂(C₁-C₆ alkyl), —C(O)NH₂, —C(O)NH(C₁-C₆ alkyl),—C(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆ alkyl)C(O)(C₁-C₆ alkyl), —NHC(O)(C₁-C₆alkyl), —NHSO₂(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)SO₂(C₁-C₆ alkyl), —SO₂NH₂,—SO₂NH(C₁-C₆ alkyl), —SO₂N(C₁-C₆ alkyl)₂, —OC(O)NH₂, —OC(O)NH(C₁-C₆alkyl), —OC(O)N(C₁-C₆ alkyl)₂, —OC(O)O(C₁-C₆ alkyl), —NHC(O)NH(C₁-C₆alkyl), —NHC(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆ alkyl)C(O)NH(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)C(O)N(C₁-C₆ alkyl)₂, —NHC(O)NH(C₁-C₆ alkyl),—NHC(O)N(C₁-C₆ alkyl)₂, —NHC(O)O(C₁-C₆ alkyl), and —N(C₁-C₆alkyl)C(O)O(C₁-C₆ alkyl);

or R¹⁶ and R¹⁷ together with the nitrogen to which they are attachedform a 3-8 membered saturated, unsaturated or aromatic ring having 0-2heteroatoms selected from O, S and N, wherein said ring is optionallysubstituted with one or more groups selected from halo, CN, —OCF₃, CF₃,—NO₂, C₁-C₆ alkyl, —OH, —SH, —O(C₁-C₆ alkyl), —S(C₁-C₆ alkyl), —NH₂,—NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —SO₂(C₁-C₆ alkyl), —CO₂H, —CO₂(C₁-C₆alkyl), —C(O)NH₂, —C(O)NH(C₁-C₆ alkyl), —C(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆alkyl)C(O)(C₁-C₆ alkyl), —NHC(O)(C₁-C₆ alkyl), —NHSO₂(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)SO₂(C₁-C₆ alkyl), —SO₂NH₂, —SO₂NH(C₁-C₆ alkyl),—SO₂N(C₁-C₆ alkyl)₂, —OC(O)NH₂, —OC(O)NH(C₁-C₆ alkyl), —OC(O)N(C₁-C₆alkyl)₂, —OC(O)O(C₁-C₆ alkyl), —NHC(O)NH(C₁-C₆ alkyl), —NHC(O)N(C₁-C₆alkyl)₂, —N(C₁-C₆ alkyl)C(O)NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)C(O)N(C₁-C₆alkyl)₂, —NHC(O)NH(C₁-C₆ alkyl), —NHC(O)N(C₁-C₆ alkyl)₂, —NHC(O)O(C₁-C₆alkyl), and —N(C₁-C₆ alkyl)C(O)O(C₁-C₆ alkyl);

R¹⁹ and R²⁰ are independently selected from H, C₁-C₁₂ alkyl,—(CH₂)_(n)-aryl, —(CH₂)_(n)-carbocyclyl, —(CH₂)_(n)-heterocyclyl, and—(CH₂)_(n)-heteroaryl;

R²¹ is C₁-C₁₂ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, carbocyclyl,heterocyclyl, aryl, or heteroaryl, wherein each member of R²¹ isoptionally substituted with one or more groups selected from halo, oxo,CN, —OCF₃, CF₃, —NO₂, C₁-C₆ alkyl, —OH, —SH, —O(C₁-C₆ alkyl), —S(C₁-C₆alkyl), —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —SO₂(C₁-C₆ alkyl),—CO₂H, —CO₂(C₁-C₆ alkyl), —C(O)NH₂, —C(O)NH(C₁-C₆ alkyl), —C(O)N(C₁-C₆alkyl)₂, —N(C₁-C₆ alkyl)C(O)(C₁-C₆ alkyl), —NHC(O)(C₁-C₆ alkyl),—NHSO₂(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)SO₂(C₁-C₆ alkyl), —SO₂NH₂,—SO₂NH(C₁-C₆ alkyl), —SO₂N(C₁-C₆ alkyl)₂, —OC(O)NH₂, —OC(O)NH(C₁-C₆alkyl), —OC(O)N(C₁-C₆ alkyl)₂, —OC(O)O(C₁-C₆ alkyl), —NHC(O)NH(C₁-C₆alkyl), —NHC(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆ alkyl)C(O)NH(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)C(O)N(C₁-C₆ alkyl)₂, —NHC(O)NH(C₁-C₆ alkyl),—NHC(O)N(C₁-C₆ alkyl)₂, —NHC(O)O(C₁-C₆ alkyl), and —N(C₁-C₆alkyl)C(O)O(C₁-C₆ alkyl);

each Y′ is independently O, NR²², or S; and

R²² is H or C₁-C₁₂ alkyl.

The present invention includes a composition (e.g., a pharmaceuticalcomposition) comprising a compound of formula I (and/or solvates,hydrates and/or salts thereof) and a carrier (a pharmaceuticallyacceptable carrier). The present invention also includes a composition(e.g., a pharmaceutical composition) comprising a compound of formula I(and/or solvates, hydrates and/or salts thereof) and a carrier (apharmaceutically acceptable carrier), further comprising a secondchemotherapeutic and/or a second anti-inflammatory agent. The presentcompositions are useful for inhibiting abnormal cell growth or treatinga hyperproliferative disorder in a mammal (e.g., human). The presentcompositions are also useful for treating inflammatory diseases in amammal (e.g., human).

The present invention includes a method of inhibiting abnormal cellgrowth or treating a hyperproliferative disorder in a mammal (e.g.,human) comprising administering to said mammal a therapeuticallyeffective amount of a compound of formula I (and/or solvates and saltsthereof) or a composition thereof, alone or in combination with a secondchemotherapeutic agent.

The present invention includes a method of treating an inflammatorydisease in a mammal (e.g., human) comprising administering to saidmammal a therapeutically effective amount of a compound of formula I(and/or solvates and salts thereof) or a composition thereof, alone orin combination with a second anti-inflammatory agent.

The present invention includes a method of using the present compoundsfor in vitro, in situ, and in vivo diagnosis or treatment of mammaliancells, organisms, or associated pathological conditions.

DETAILED DESCRIPTION OF EXEMPLARY EMBODIMENTS

Reference will now be made in detail to certain embodiments of theinvention, examples of which are illustrated in the accompanyingstructures and formulae. While the invention will be described inconjunction with the enumerated embodiments, it will be understood thatthey are not intended to limit the invention to those embodiments. Onthe contrary, the invention is intended to cover all alternatives,modifications, and equivalents which may be included within the scope ofthe present invention as defined by the claims. One skilled in the artwill recognize many methods and materials similar or equivalent to thosedescribed herein, which could be used in the practice of the presentinvention. The present invention is in no way limited to the methods andmaterials described. In the event that one or more of the incorporatedliterature, patents, and similar materials differs from or contradictsthis application, including but not limited to defined terms, termusage, described techniques, or the like, this application controls.

Definitions

The term “alkyl” as used herein refers to a saturated linear orbranched-chain monovalent hydrocarbon radical of one to twelve carbonatoms. Examples of alkyl groups include, but are not limited to, methyl(Me, —CH₃), ethyl (Et, —CH₂CH₃), 1-propyl (n-Pr, n-propyl, —CH₂CH₂CH₃),2-propyl (i-Pr, i-propyl, —CH(CH₃)₂), 1-butyl (n-Bu, n-butyl,—CH₂CH₂CH₂CH₃), 2-methyl-1-propyl (1-Bu, i-butyl, —CH₂CH(CH₃)₂), 2-butyl(s-Bu, s-butyl, —CH(CH₃)CH₂CH₃), 2-methyl-2-propyl (t-Bu, t-butyl,—C(CH₃)₃), 1-pentyl (n-pentyl, —CH₂CH₂CH₂CH₂CH₃), 2-pentyl(—CH(CH₃)CH₂CH₂CH₃), 3-pentyl (—CH(CH₂CH₃)₂), 2-methyl-2-butyl(—C(CH₃)₂CH₂CH₃), 3-methyl-2-butyl (—CH(CH₃)CH(CH₃)₂), 3-methyl-1-butyl(—CH₂CH₂CH(CH₃)₂), 2-methyl-1-butyl (—CH₂CH(CH₃)CH₂CH₃), 1-hexyl(—CH₂CH₂CH₂CH₂CH₂CH₃), 2-hexyl (—CH(CH₃)CH₂CH₂CH₂CH₃), 3-hexyl(—CH(CH₂CH₃)(CH₂CH₂CH₃)), 2-methyl-2-pentyl (—C(CH₃)₂CH₂CH₂CH₃),3-methyl-2-pentyl (—CH(CH₃)CH(CH₃)CH₂CH₃), 4-methyl-2-pentyl(—CH(CH₃)CH₂CH(CH₃)₂), 3-methyl-3-pentyl (—C(CH₃)(CH₂CH₃)₂),2-methyl-3-pentyl (—CH(CH₂CH₃)CH(CH₃)₂), 2,3-dimethyl-2-butyl(—C(CH₃)₂CH(CH₃)₂), 3,3-dimethyl-2-butyl (—CH(CH₃)C(CH₃)₃, 1-heptyl,1-octyl, and the like.

The term “alkenyl” refers to linear or branched-chain monovalenthydrocarbon radical of two to twelve carbon atoms with at least one siteof unsaturation, i.e., a carbon-carbon, sp² double bond, wherein thealkenyl radical includes radicals having “cis” and “trans” orientations,or alternatively, “E” and “Z” orientations. Examples include, but arenot limited to, ethylenyl or vinyl (—CH═CH₂), allyl (—CH₂CH═CH₂), andthe like.

The term “alkynyl” refers to a linear or branched monovalent hydrocarbonradical of two to twelve carbon atoms with at least one site ofunsaturation, i.e., a carbon-carbon, sp triple bond. Examples include,but are not limited to, ethynyl (—C≡CH), propynyl (propargyl, —CH₂C≡CH),and the like.

The terms “carbocycle”, “carbocyclyl”, “carbocyclic ring” and“cycloalkyl” refer to a monovalent non-aromatic, saturated or partiallyunsaturated ring having 3 to 12 carbon atoms as a monocyclic ring or 7to 12 carbon atoms as a bicyclic ring. Bicyclic carbocycles having 7 to12 atoms can be arranged, for example, as a bicyclo[4,5], [5,5], [5,6]or [6,6] system, and bicyclic carbocycles having 9 or 10 ring atoms canbe arranged as a bicyclo[5,6] or [6,6] system, or as bridged systemssuch as bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane andbicyclo[3.2.2]nonane. Examples of monocyclic carbocycles include, butare not limited to, cyclopropyl, cyclobutyl, cyclopentyl,1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl,1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl,cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl,cycloundecyl, cyclododecyl, and the like.

“Aryl” means a monovalent aromatic hydrocarbon radical of 6-18 carbonatoms derived by the removal of one hydrogen atom from a single carbonatom of a parent aromatic ring system. Some aryl groups are representedin the exemplary structures as “Ar”. Aryl includes bicyclic radicalscomprising an aromatic ring fused to a saturated, partially unsaturatedring, or aromatic carbocyclic or heterocyclic ring. Typical aryl groupsinclude, but are not limited to, radicals derived from benzene (phenyl),substituted benzenes, naphthalene, anthracene, indenyl, indanyl,1,2-dihydronaphthalene, 1,2,3,4-tetrahydronaphthyl, and the like.

The terms “heterocycle,” “heterocyclyl” and “heterocyclic ring” are usedinterchangeably herein and refer to a saturated or a partiallyunsaturated (i.e., having one or more double and/or triple bonds withinthe ring) carbocyclic radical of 3 to 18 ring atoms in which at leastone ring atom is a heteroatom selected from nitrogen, oxygen and sulfur,the remaining ring atoms being C, where one or more ring atoms isoptionally substituted independently with one or more substituentsdescribed below. A heterocycle may be a monocycle having 3 to 7 ringmembers (2 to 6 carbon atoms and 1 to 4 heteroatoms selected from N, O,P, and S) or a bicycle having 7 to 10 ring members (4 to 9 carbon atomsand 1 to 6 heteroatoms selected from N, O, P, and S), for example: abicyclo[4,5], [5,5], [5,6], or [6,6] system. Heterocycles are describedin Paquette, Leo A.; “Principles of Modern Heterocyclic Chemistry” (W.A.Benjamin, New York, 1968), particularly Chapters 1, 3, 4, 6, 7, and 9;“The Chemistry of Heterocyclic Compounds, A series of Monographs” (JohnWiley & Sons, New York, 1950 to present), in particular Volumes 13, 14,16, 19, and 28; and J. Am. Chem. Soc. (1960) 82:5566. “Heterocyclyl”also includes radicals where heterocycle radicals are fused with asaturated, partially unsaturated ring, or aromatic carbocyclic orheterocyclic ring. Examples of heterocyclic rings include, but are notlimited to, pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl,tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl,tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl,thioxanyl, piperazinyl, homopiperazinyl, azetidinyl, oxetanyl,thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl,thiazepinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl,4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl,dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl,pyrazolidinylimidazolinyl, imidazolidinyl, 3-azabicyco[3.1.0]hexanyl,3-azabicyclo[4.1.0]heptanyl, and azabicyclo[2.2.2]hexanyl. Spiromoieties are also included within the scope of this definition. Examplesof a heterocyclic group wherein ring atoms are substituted with oxo (═O)moieties are pyrimidinonyl and 1,1-dioxo-thiomorpholinyl.

The term “heteroaryl” refers to a monovalent aromatic radical of 5- or6-membered rings, and includes fused ring systems (at least one of whichis aromatic) of 5-18 atoms, containing one or more heteroatomsindependently selected from nitrogen, oxygen, and sulfur. Examples ofheteroaryl groups are pyridinyl (including, for example,2-hydroxypyridinyl), imidazolyl, imidazopyridinyl, pyrimidinyl(including, for example, 4-hydroxypyrimidinyl), pyrazolyl, triazolyl,pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl,isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl,benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl,phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl,oxadiazolyl, triazolyl, thiadiazolyl, furazanyl, benzofurazanyl,benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl,quinoxalinyl, naphthyridinyl, and furopyridinyl.

The heterocycle or heteroaryl groups may be carbon (carbon-linked) ornitrogen (nitrogen-linked) attached where such is possible. By way ofexample and not limitation, carbon bonded heterocycles or heteroarylsare bonded at position 2, 3, 4, 5, or 6 of a pyridine, position 3, 4, 5,or 6 of a pyridazine, position 2, 4, 5, or 6 of a pyrimidine, position2, 3, 5, or 6 of a pyrazine, position 2, 3, 4, or 5 of a furan,tetrahydrofuran, thiofuran, thiophene, pyrrole or tetrahydropyrrole,position 2, 4, or 5 of an oxazole, imidazole or thiazole, position 3, 4,or 5 of an isoxazole, pyrazole, or isothiazole, position 2 or 3 of anaziridine, position 2, 3, or 4 of an azetidine, position 2, 3, 4, 5, 6,7, or 8 of a quinoline or position 1, 3, 4, 5, 6, 7, or 8 of anisoquinoline.

By way of example and not limitation, nitrogen bonded heterocycles orheteroaryls are bonded at position 1 of an aziridine, azetidine,pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole,imidazolidine, 2-imidazoline, 3-imidazoline, pyrazole, pyrazoline,2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, indoline,1H-indazole, position 2 of a isoindole, or isoindoline, position 4 of amorpholine, and position 9 of a carbazole, or β-carboline.

The term “halo” refers to F, Cl, Br or I. The heteroatoms present inheteroaryl or heterocycicyl include the oxidized forms such as N⁺→O⁻,S(O) and S(O)₂.

The terms “treat” and “treatment” refer to both therapeutic treatmentand prophylactic or preventative measures, wherein the object is toprevent or slow down (lessen) an undesired physiological change ordisorder, such as the development or spread of cancer. For purposes ofthis invention, beneficial or desired clinical results include, but arenot limited to, alleviation of symptoms, diminishment of extent ofdisease, stabilized (i.e., not worsening) state of disease, delay orslowing of disease progression, amelioration or palliation of thedisease state, and remission (whether partial or total), whetherdetectable or undetectable. “Treatment” can also mean prolongingsurvival as compared to expected survival if not receiving treatment.Those in need of treatment include those already with the condition ordisorder as well as those prone to have the condition or disorder orthose in which the condition or disorder is to be prevented.

The phrase “therapeutically effective amount” means an amount of acompound of the present invention that (i) treats or prevents theparticular disease, condition, or disorder, (ii) attenuates,ameliorates, or eliminates one or more symptoms of the particulardisease, condition, or disorder, or (iii) prevents or delays the onsetof one or more symptoms of the particular disease, condition, ordisorder described herein. In the case of cancer, the therapeuticallyeffective amount of the drug may reduce the number of cancer cells;reduce the tumor size; inhibit (i.e., slow to some extent and preferablystop) cancer cell infiltration into peripheral organs; inhibit (i.e.,slow to some extent and preferably stop) tumor metastasis; inhibit, tosome extent, tumor growth; and/or relieve to some extent one or more ofthe symptoms associated with the cancer. To the extent the drug mayprevent growth and/or kill existing cancer cells, it may be cytostaticand/or cytotoxic. For cancer therapy, efficacy can be measured, forexample, by assessing the time to disease progression (TTP) and/ordetermining the response rate (RR).

The terms “abnormal cell growth” and “hyperproliferative disorder” areused interchangeably in this application. “Abnormal cell growth”, asused herein, unless otherwise indicated, refers to cell growth that isindependent of normal regulatory mechanisms (e.g., loss of contactinhibition). This includes, for example, the abnormal growth of: (1)tumor cells (tumors) that proliferate by expressing a mutated tyrosinekinase or overexpression of a receptor tyrosine kinase; (2) benign andmalignant cells of other proliferative diseases in which aberranttyrosine kinase activation occurs; (3) any tumors that proliferate byreceptor tyrosine kinases; (4) any tumors that proliferate by aberrantserine/threonine kinase activation; and (5) benign and malignant cellsof other proliferative diseases in which aberrant serine/threoninekinase activation occurs.

The terms “cancer” and “cancerous” refer to or describe thephysiological condition in mammals that is typically characterized byunregulated cell growth. A “tumor” comprises one or more cancerouscells. Examples of cancer include, but are not limited to, carcinoma,lymphoma, blastoma, sarcoma, and leukemia or lymphoid malignancies. Moreparticular examples of such cancers include squamous cell cancer (e.g.,epithelial squamous cell cancer), lung cancer including small-cell lungcancer, non-small cell lung cancer (“NSCLC”), adenocarcinoma of the lungand squamous carcinoma of the lung, cancer of the peritoneum,hepatocellular cancer, gastric or stomach cancer includinggastrointestinal cancer, pancreatic cancer, glioblastoma, cervicalcancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, breastcancer, colon cancer, rectal cancer, colorectal cancer, endometrial oruterine carcinoma, salivary gland carcinoma, kidney or renal cancer,prostate cancer, vulval cancer, thyroid cancer, hepatic carcinoma, analcarcinoma, penile carcinoma, acute leukemia, as well as head/brain andneck cancer.

A “chemotherapeutic agent” is a compound useful in the treatment ofcancer. Examples of chemotherapeutic agents include Erlotinib (TARCEVA®,Genentech/OSI Pharm.), Bortezomib (VELCADE®, Millennium Pharm.),Fulvestrant (FASLODEX®, AstraZeneca), Sutent (SU11248, Pfizer),Letrozole (FEMARA®, Novartis), Imatinib mesylate (GLEEVEC®, Novartis),PTK787/ZK 222584 (Novartis), Oxaliplatin (Eloxatin®, Sanofi), 5-FU(5-fluorouracil), Leucovorin, Rapamycin (Sirolimus, RAPAMUNE®, Wyeth),Lapatinib (TYKF.RB®, GSK572016, Glaxo Smith Kline), Lonafarnib (SCH66336), Sorafenib (BAY43-9006, Bayer Labs), and Gefitinib (IRESSA®,AstraZeneca), AG1478, AG1571 (SU 5271; Sugen), alkylating agents such asthiotepa and CYTOXAN® cyclosphosphamide; alkyl sulfonates such asbusulfan, improsulfan and piposulfan; aziridines such as benzodopa,carboquone, meturedopa, and uredopa; ethylenimines and methylamelaminesincluding altretamine, triethylenemelamine, triethylenephosphoramide,triethylenethiophosphoramide and trimethylomelamine; acetogenins(especially bullatacin and bullatacinone); a camptothecin (including thesynthetic analog topotecan); bryostatin; callystatin; CC-1065 (includingits adozelesin, carzelesin and bizelesin synthetic analogs);cryptophycins (particularly cryptophycin 1 and cryptophycin 8);dolastatin; duocarmycin (including the synthetic analogs, KW-2189 andCB1-TM1); eleutherobin; pancratistatin; a sarcodictyin; spongistatin;nitrogen mustards such as chlorambucil, chlornaphazine,chlorophosphamide, estramustine, ifosfamide, mechlorethamine,mechlorethamine oxide hydrochloride, melphalan, novembichin,phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosureassuch as carmustine, chlorozotocin, fotemustine, lomustine, nimustine,and ranimnustine; antibiotics such as the enediyne antibiotics (e.g.,calicheamicin, especially calicheamicin gamma1I and calicheamicinomegaI1 (Angew Chem. Intl. Ed. Engl. (1994) 33:183-186); dynemicin,including dynemicin A; bisphosphonates, such as clodronate; anesperamicin; as well as neocarzinostatin chromophore and relatedchromoprotein enediyne antibiotic chromophores), aclacinomysins,actinomycin, authramycin, azaserine, bleomycins, cactinomycin,carabicin, caminomycin, carzinophilin, chromomycinis, dactinomycin,daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, ADRIAMYCIN®(doxorubicin), morpholino-doxorubicin, cyanomorpholino-doxorubicin,2-pyrrolino-doxorubicin and deoxydoxorubicin), epirubicin, esorubicin,idarubicin, marcellomycin, mitomycins such as mitomycin C, mycophenolicacid, nogalamycin, olivomycins, peplomycin, porfiromycin, puromycin,quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin,ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexateand 5-fluorouracil (5-FU); folic acid analogs such as denopterin,methotrexate, pteropterin, trimetrexate; purine analogs such asfludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidineanalogs such as ancitabine, azacitidine, 6-azauridine, carmofur,cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine;androgens such as calusterone, dromostanolone propionate, epitiostanol,mepitiostane, testolactone; anti-adrenals such as aminoglutethimide,mitotane, trilostane; folic acid replenisher such as frolinic acid;aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil;amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine;diaziquone; elformithine; elliptinium acetate; an epothilone; etoglucid;gallium nitrate; hydroxyurea; lentinan; lonidainine; maytansinoids suchas maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidanmol;nitraerine; pentostatin; phenamet; pirarubicin; losoxantrone;podophyllinic acid; 2-ethylhydrazide; procarbazine; PSK® polysaccharidecomplex (JHS Natural Products, Eugene, Oreg.); razoxane; rhizoxin;sizofuran; spirogermanium; tenuazonic acid; triaziquone;2,2′,2″-trichlorotriethylamine; trichothecenes (especially T-2 toxin,verracurin A, roridin A and anguidine); urethan; vindesine; dacarbazine;mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine;arabinoside (“Ara-C”); cyclophosphamide; thiotepa; taxoids, e.g., TAXOL®(paclitaxel; Bristol-Myers Squibb Oncology, Princeton, N.J.), ABRAXANE™(Cremophor-free), albumin-engineered nanoparticle formulations ofpaclitaxel (American Pharmaceutical Partners, Schaumberg, Ill.), andTAXOTERE® (doxetaxel; Rhone-Poulenc Rorer, Antony, France);chloranmbucil; GEMZAR® (gemcitabine); 6-thioguanine; mercaptopurine;methotrexate; platinum analogs such as cisplatin and carboplatin;vinblastine; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine;NAVELBINE® (vinorelbine); novantrone; teniposide; edatrexate;daunomycin; aminopterin; capecitabine (XELODA®); ibandronate; CPT-11;topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO);retinoids such as retinoic acid; and pharmaceutically acceptable salts,acids and derivatives of any of the above.

Also included in the definition of “chemotherapeutic agent” are: (i)anti-hormonal agents that act to regulate or inhibit hormone action ontumors such as anti-estrogens and selective estrogen receptor modulators(SERMs), including, for example, tamoxifen (including NOLVADEX®;tamoxifen citrate), raloxifene, droloxifene, 4-hydroxytamoxifen,trioxifene, keoxifene, LY117018, onapristone, and FARESTON® (toremifinecitrate); (ii) aromatase inhibitors that inhibit the enzyme aromatase,which regulates estrogen production in the adrenal glands, such as, forexample, 4(5)-imidazoles, aminoglutethimide, MEGASE® (megestrolacetate), AROMASIN® (exemestane; Pfizer), formestanie, fadrozole,RIVISOR® (vorozole), FEMARA® (letrozole; Novartis), and ARIMIDEX®(anastrozole; AstraZeneca); (iii) anti-androgens such as flutamide,nilutamide, bicalutamide, leuprolide, and goserelin; as well astroxacitabine (a 1,3-dioxolane nucleoside cytosine analog); (iv) proteinkinase inhibitors; (v) lipid kinase inhibitors; (vi) antisenseoligonucleotides, particularly those which inhibit expression of genesin signaling pathways implicated in aberrant cell proliferation, suchas, for example, PKC-alpha, Ralf and H-Ras; (vii) ribozymes such as VEGFexpression inhibitors (e.g., ANGIOZYME®) and HER2 expression inhibitors;(viii) vaccines such as gene therapy vaccines, for example, ALLOVECTIN®,LEUVECTIN®, and VAXID®; PROLEUKIN® rIL-2; a topoisomerase 1 inhibitorsuch as LURTOTECAN®; ABARELIX® rmRH; (ix) anti-angiogenic agents such asbevacizumab (AVASTIN®, Genentech); and (x) pharmaceutically acceptablesalts, acids and derivatives of any of the above. Other anti-angiogenicagents include MMP-2 (matrix-metalloproteinase 2) inhibitors, MMP-9(matrix-metalloproteinase 9) inhibitors, COX-II (cyclooxygenase II)inhibitors, and VEGF receptor tyrosine kinase inhibitors. Examples ofsuch useful matrix metalloproteinase inhibitors that can be used incombination with the present compounds/compositions (such as any one ofthe title compounds of EXAMPLES 5-25) are described in WO 96/33172, WO96/27583, EP 818442, EP 1004578, WO 98/07697, WO 98/03516, WO 98/34918,WO 98/34915, WO 98/33768, WO 98/30566, EP 606,046, EP 931,788, WO90/05719, WO 99/52910, WO 99/52889, WO 99/29667, WO 99/07675, EP 945864,U.S. Pat. No. 5,863,949, U.S. Pat. No. 5,861,510, and EP 780,386, all ofwhich are incorporated herein in their entireties by reference. Examplesof VEGF receptor tyrosine kinase inhibitors include4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline(ZD6474; Example 2 within WO 01/32651),4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)-quinazoline(AZD2171; Example 240 within WO 00/47212), vatalanib (PTK787; WO98/35985) and SU11248 (sunitinib; WO 01/60814), and compounds such asthose disclosed in PCT Publication Nos. WO 97/22596, WO 97/30035, WO97/32856, and WO 98/13354).

Other examples of chemotherapeutic agents that can be used incombination with the present compounds (such as any one of the titlecompounds of EXAMPLES 5-25) include inhibitors of PI3K(phosphoinositide-3 kinase), such as those reported in Yaguchi et al(2006) Jour. of the Nat. Cancer Inst. 98(8):545-556; U.S. Pat. No.7,173,029; U.S. Pat. No. 7,037,915; U.S. Pat. No. 6,608,056; U.S. Pat.No. 6,608,053; U.S. Pat. No. 6,838,457; U.S. Pat. No. 6,770,641; U.S.Pat. No. 6,653,320; U.S. Pat. No. 6,403,588; US 2008/0242665; WO2006/046031; WO 2006/046035; WO 2006/046040; WO 2007/042806; WO2007/042810; WO 2004/017950; US 2004/092561; WO 2004/007491; WO2004/006916; WO 2003/037886; US 2003/149074; WO 2003/035618; WO2003/034997; US 2003/158212; EP 1417976; US 2004/053946; JP 2001247477;JP 08175990; JP 08176070; U.S. Pat. No. 6,703,414; and WO 97/15658, allof which are incorporated herein in their entireties by reference.Specific examples of such PI3K inhibitors include SF-1126 (PI3Kinhibitor, Semafore Pharmaceuticals), BEZ-235 (PI3K inhibitor,Novartis), XL-147 (PI3K inhibitor, Exelixis, Inc.), and GDC-0941 (PI3Kinhibitor, Genentech, Inc.).

The term “inflammatory diseases” as used in this application includes,but not limited to, rheumatoid arthritis, atherosclerosis, congestivehear failure, inflammatory bowel disease (including, but not limited to,Crohn's disease and ulcerative colitis), chronic obstructive pulmonarydisease in the lung, fibrotic disease in the liver and kidney, Crohn'sdisease, lupus, skin diseases such as psoriasis, eczema and scleroderma,osteoarthritis, multiple sclerosis, asthma, diseases and disordersrelated to diabetic complications, fibrotic organ failure in organs suchas lung, liver, kidney, and inflammatory complications of thecardiovascular system such as acute coronary syndrome.

An “anti-inflammatory agent” is a compound useful in the treatment ofinflammation. Examples of anti-inflammatory agents include injectableprotein therapeutics such as Enbrel®, Remicade®, Humira® and Kineret®.Other examples of anti-inflammatory agents include non-steroidalanti-inflammatory agents (NSAIDs), such as ibuprofen or aspirin (whichreduce swelling and alleviate pain); disease-modifying anti-rheumaticdrugs (DMARDs) such as methotrexate; 5-aminosalicylates (sulfasalazineand the sulfa-free agents); corticosteroids; immunomodulators such as6-mercaptoputine (“6-MP”), azathioprine (“AZA”), cyclosporines, andbiological response modifiers such as Remicade® (infliximab) and Enbrel®(etanercept); fibroblast growth factors; platelet derived growthfactors; enzyme blockers such as Arava® (leflunomide); and/or acartilage protecting agent such as hyaluronic acid, glucosamine, andchondroitin.

The term “prodrug” as used in this application refers to a precursor orderivative form of a compound of the invention that is capable of beingenzymatically or hydrolytically activated or converted into the moreactive parent form. See, e.g., Wilman, “Prodrugs in Cancer Chemotherapy”Biochemical Society Transactions, 14, pp. 375-382, 615th Meeting Belfast(1986) and Stella et al., “Prodrugs: A Chemical Approach to TargetedDrug Delivery,” Directed Drug Delivery, Borchardt et al., (ed.), pp.247-267, Humana Press (1985). The prodrugs of this invention include,but are not limited to, ester-containing prodrugs, phosphate-containingprodrugs, thiophosphate-containing prodrugs, sulfate-containingprodrugs, peptide-containing prodrugs, D-amino acid-modified prodrugs,glycosylated prodrugs, β-lactam-containing prodrugs, optionallysubstituted phenoxyacetamide-containing prodrugs, optionally substitutedphenylacetamide-containing prodrugs, 5-fluorocytosine and other5-fluorouridine prodrugs which can be converted into the more activecytotoxic free drug. Examples of cytotoxic drugs that can be derivatizedinto a prodrug form for use in this invention include, but are notlimited to, compounds of the invention and chemotherapeutic agents suchas described above.

A “metabolite” is a product produced through metabolism in the body of aspecified compound or salt thereof. Metabolites of a compound may beidentified using routine techniques known in the art and theiractivities determined using tests such as those described herein. Suchproducts may result for example from the oxidation, hydroxylation,reduction, hydrolysis, amidation, deamidation, esterification,deesterification, enzymatic cleavage, and the like, of the administeredcompound. Accordingly, the invention includes metabolites of compoundsof the invention, including compounds produced by a process comprisingcontacting a compound of this invention with a mammal for a period oftime sufficient to yield a metabolic product thereof.

A “liposome” is a small vesicle composed of various types of lipids,phospholipids and/or surfactant which is useful for delivery of a drug(such as the MEK inhibitors disclosed herein and, optionally, achemotherapeutic agent) to a mammal. The components of the liposome arecommonly arranged in a bilayer formation, similar to the lipidarrangement of biological membranes.

The term “package insert” is used to refer to instructions customarilyincluded in commercial packages of therapeutic products, that containinformation about the indications, usage, dosage, administration,contraindications and/or warnings concerning the use of such therapeuticproducts.

The term “chiral” refers to molecules which have the property ofnon-superimposability of the mirror image partner, while the term“achiral” refers to molecules which are superimposable on their mirrorimage partner.

The term “stereoisomer” refers to compounds which have identicalchemical constitution and connectivity, but different orientations oftheir atoms in space that cannot be interconverted by rotation aboutsingle bonds.

“Diastereomer” refers to a stereoisomer with two or more centers ofchirality and whose molecules are not mirror images of one another.Diastereomers have different physical properties, e.g. melting points,boiling points, spectral properties, and reactivities. Mixtures ofdiastereomers may separate under high resolution analytical proceduressuch as crystallization, electrophoresis and chromatography.

“Enantiomers” refer to two stereoisomers of a compound which arenon-superimposable mirror images of one another.

Stereochemical definitions and conventions used herein generally followS. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984)McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S.,“Stereochemistry of Organic Compounds”, John Wiley & Sons, Inc., NewYork, 1994. The compounds of the invention may contain asymmetric orchiral centers, and therefore exist in different stereoisomeric forms.It is intended that all stereoisomeric forms of the compounds of theinvention, including but not limited to, diastereomers, enantiomers andatropisomers, as well as mixtures thereof such as racemic mixtures, formpart of the present invention. Many organic compounds exist in opticallyactive forms, i.e., they have the ability to rotate the plane ofplane-polarized light. In describing an optically active compound, theprefixes D and L, or R and S, are used to denote the absoluteconfiguration of the molecule about its chiral center(s). The prefixes dand l or (+) and (−) are employed to designate the sign of rotation ofplane-polarized light by the compound, with (−) or l meaning that thecompound is levorotatory. A compound prefixed with (+) or d isdextrorotatory. For a given chemical structure, these stereoisomers areidentical except that they are mirror images of one another. A specificstereoisomer may also be referred to as an enantiomer, and a mixture ofsuch isomers is often called an enantiomeric mixture. A 50:50 mixture ofenantiomers is referred to as a racemic mixture or a racemate, which mayoccur where there has been no stereoselection or stereospecificity in achemical reaction or process. The terms “racemic mixture” and “racemate”refer to an equimolar mixture of two enantiomeric species, devoid ofoptical activity.

The term “tautomer” or “tautomeric form” refers to structural isomers ofdifferent energies which are interconvertible via a low energy barrier.For example, proton tautomers (also known as prototropic tautomers)include interconversions via migration of a proton, such as keto-enoland imine-enamine isomerizations. Valence tautomers includeinterconversions by reorganization of some of the bonding electrons.

The phrase “pharmaceutically acceptable salt” as used herein, refers topharmaceutically acceptable organic or inorganic salts of a compound ofthe invention. Exemplary salts include, but are not limited, to sulfate,citrate, acetate, oxalate, chloride, bromide, iodide, nitrate,bisulfate, phosphate, acid phosphate, isonicotinate, lactate,salicylate, acid citrate, tartrate, oleate, tannate, pantothenate,bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate,gluconate, glucuronate, saccharate, formate, benzoate, glutamate,methanesulfonate “mesylate”, ethanesulfonate, benzenesulfonate,p-toluenesulfonate, pamoate (i.e.,1,1′-methylene-bis-(2-hydroxy-3-naphthoate)) salts, alkali metal (e.g.,sodium and potassium) salts, alkaline earth metal (e.g., magnesium)salts, and ammonium salts. A pharmaceutically acceptable salt mayinvolve the inclusion of another molecule such as an acetate ion, asuccinate ion or other counter ion. The counter ion may be any organicor inorganic moiety that stabilizes the charge on the parent compound.Furthermore, a pharmaceutically acceptable salt may have more than onecharged atom in its structure. Instances where multiple charged atomsare part of the pharmaceutically acceptable salt can have multiplecounter ions. Hence, a pharmaceutically acceptable salt can have one ormore charged atoms and/or one or more counter ion.

If the compound of the invention is a base, the desired pharmaceuticallyacceptable salt may be prepared by any suitable method available in theart, for example, treatment of the free base with an inorganic acid,such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,methanesulfonic acid, phosphoric acid and the like, or with an organicacid, such as acetic acid, maleic acid, succinic acid, mandelic acid,fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid,salicylic acid, a pyranosidyl acid, such as glucuronic acid orgalacturonic acid, an alpha hydroxy acid, such as citric acid ortartaric acid, an amino acid, such as aspartic acid or glutamic acid, anaromatic acid, such as benzoic acid or cinnamic acid, a sulfonic acid,such as p-toluenesulfonic acid or ethanesulfonic acid, or the like.

If the compound of the invention is an acid, the desiredpharmaceutically acceptable salt may be prepared by any suitable method,for example, treatment of the free acid with an inorganic or organicbase, such as an amine (primary, secondary or tertiary), an alkali metalhydroxide or alkaline earth metal hydroxide, or the like. Illustrativeexamples of suitable salts include, but are not limited to, organicsalts derived from amino acids, such as glycine and arginine, ammonia,primary, secondary, and tertiary amines, and cyclic amines, such aspiperidine, morpholine and piperazine, and inorganic salts derived fromsodium, calcium, potassium, magnesium, manganese, iron, copper, zinc,aluminum and lithium.

The phrase “pharmaceutically acceptable” indicates that the substance orcomposition must be compatible chemically and/or toxicologically, withthe other ingredients comprising a formulation, and/or the mammal beingtreated therewith.

A “solvate” refers to an association or complex of one or more solventmolecules and a compound of the invention. Examples of solvents thatform solvates include, but are not limited to, water, isopropanol,ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine.The term “hydrate” refers to the complex where the solvent molecule iswater.

The term “protecting group” refers to a substituent that is commonlyemployed to block or protect a particular functionality while reactingother functional groups on the compound. For example, an“amino-protecting group” is a substituent attached to an amino groupthat blocks or protects the amino functionality in the compound.Suitable amino-protecting groups include acetyl, trifluoroacetyl,t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBZ) and9-fluorenylmethylenoxycarbonyl (Fmoc). Similarly, a “hydroxy-protectinggroup” refers to a substituent of a hydroxy group that blocks orprotects the hydroxy functionality. Suitable protecting groups includeacetyl and trialkylsilyl. A “carboxy-protecting group” refers to asubstituent of the carboxy group that blocks or protects the carboxyfunctionality. Common carboxy-protecting groups includephenylsulfonylethyl, cyanoethyl, 2-(trimethylsilyl)ethyl,2-(trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl,2-(p-nitrophenylsulfenyl)ethyl, 2-(diphenylphosphino)-ethyl, nitroethyland the like. For a general description of protecting groups and theiruse, see T. W. Greene, Protective Groups in Organic Synthesis, JohnWiley & Sons, New York, 1991.

The terms “compound of this invention”, “compounds of the presentinvention” “compounds of formula I”, “imidazopyridines” and“imidazopyridines of formula I”, unless otherwise indicated, includecompounds/imidazopyridines of formula I and stereoisomers, geometricisomers, tautomers, solvates, metabolites, salts (e.g., pharmaceuticallyacceptable salts) and prodrugs thereof.

The present invention provides imidazopyridines of formula I asdescribed above useful as kinase inhibitors, particularly useful as MEKkinase inhibitors. In an embodiment of the present invention, when R³ is(CR¹⁴R¹⁵)_(n)C(═O)R¹¹, —(CR¹⁴R¹⁵)_(n)NR¹¹R¹², (CR¹⁴R¹⁵)_(n)OR¹¹,—(CR¹⁴R¹⁵)_(n)SR¹¹, (CR¹⁴R¹⁵)_(n)S(O)R¹¹, or —(CR¹⁴R¹⁵)S(O)₂R¹¹; n is 0;and Z¹ is N, then said R¹¹ or R¹² is not aryl; when Z¹ is N, then R³ isnot CH₂-aryl; and all other variables are as defined in formula I.

In an embodiment of the present invention, compounds are of formula I-aor I-b and all other variables are as defined in formula I, or asdefined in the embodiment described above.

In an embodiment of the present invention, R² is H, halo, CF₃, or C₁-C₃alkyl; and all other variables are as defined in formula I, I-a or I-b,or as defined in any one of the embodiments described above.

In another embodiment of the present invention, R² is H, methyl, CF₃, F,or Cl; and all other variables are as defined in formula I, I-a or I-b,or as defined in any one of the embodiments described above.

In another embodiment of the present invention, R² is H, F or Cl; andall other variables are as defined in formula I, I-a or I-b, or asdefined in any one of the embodiments described above.

In an embodiment of the present invention, R³ is H, halo, CF₃, or C₁-C₃alkyl; and all other variables are as defined in formula I or I-a, or asdefined in any one of the embodiments described above.

In another embodiment of the present invention, R³ is H, methyl, CF₃, F,or Cl; and all other variables are as defined in formula I or I-a, or asdefined in any one of the embodiments described above.

In another embodiment of the present invention, R³ is H, F or Cl; andall other variables are as defined in formula I or I-a, or as defined inany one of the embodiments described above.

In an embodiment of the present invention, R^(P) is H or C₁-C₃ alkyl;and all other variables are as defined in formula I, I-a or I-b, or asdefined in any one of the embodiments described above. In anotherembodiment, R^(1′) is H, and all other variables are as defined informula I, I-a or I-b, or as defined in any one of the embodimentsdescribed above.

In an embodiment of the present invention, Z¹ is CR¹ and all othervariables are as defined in formula I, I-a or I-b, or as defined in anyone of the embodiments described above.

In an embodiment of the present invention, Z¹ is N and all othervariables are as defined in formula I or I-a, or as defined in any oneof the embodiments described above.

In another embodiment of the present invention, Z¹ is CR¹ and R¹ is H orC₁-C₃ alkyl; and all other variables are as defined in formula I, I-a orI-b, or as defined in any one of the embodiments described above. Inanother embodiment, R¹ is H, and all other variables are as defined informula I, I-a or I-b, or as defined in any one of the embodimentsabove. In another embodiment, R¹ is methyl, and all other variables areas defined in formula I, I-a or I-b, or as defined in any one of theembodiments above.

In an embodiment of the present invention, R⁴ is H or C₁-C₆ alkyl; andall other variables are as defined in formula I, I-a or I-b, or asdefined in any one of the embodiments above.

In another embodiment of the present invention, R⁴ is H or methyl; andall other variables are as defined in formula I, I-a or I-b, or asdefined in any one of the embodiments above. In another embodiment ofthe present invention, R⁴ is H; and all other variables are as definedin formula I, I-a or I-b, or as defined in any one of the embodimentsabove.

In an embodiment of the present invention, R⁵ is H or C₁-C₆ alkyl; andall other variables are as defined in formula I, I-a or I-b, or asdefined in any one of the embodiments above.

In another embodiment of the present invention, R⁵ is H or methyl; andall other variables are as defined in formula I, I-a or I-b, or asdefined in any one of the embodiments above.

In another embodiment of the present invention, R⁵ is H; and all othervariables are as defined in formula I, I-a or I-b, or as defined in anyone of the embodiments above.

In another embodiment of the present invention, R⁵ is methyl; and allother variables are as defined in formula I, I-a or I-b, or as definedin any one of the embodiments above.

In an embodiment of the present invention, X¹ is OR^(11′); and all othervariables are as defined in formula I, I-a or I-b; or as defined in anyone of the embodiments above.

In another embodiment of the present invention, X¹ is OR^(11′) whereinR^(11′) is H or C₁-C₁₂ alkyl (e.g., C₁-C₆ alkyl) substituted with one ormore groups independently selected from halo, CN, CF₃, —OCF₃, —NO₂, oxo,—(CR¹⁹R²⁰)_(n)C(═Y′)R¹⁶, —(CR¹⁹R²⁰)_(n)C(═Y′)OR¹⁶,—(CR¹⁹R²⁰)_(n)C(═Y′)NR¹⁶R¹⁷, —(CR¹⁹R²⁰)_(n)NR¹⁶R¹⁷, —(CR¹⁹R²⁰)_(n)OR¹⁶,—(CR¹⁹R²⁰)_(n)SR¹⁶, —(CR¹⁹R²⁰)_(n)NR¹⁶C(═Y′)R¹⁷,—(CR¹⁹R²⁰)_(n)NR¹⁶C(═Y′)OR¹⁷, —(CR¹⁹R²⁰)_(n)NR¹⁸C(═Y′)NR¹⁶R¹⁷,—(CR¹⁹R²⁰)_(n)NR¹⁷SO₂R¹⁶, —(CR¹⁹R²⁰)_(n)OC(═Y′)R¹⁶,—(CR¹⁹R²⁰)_(n)OC(═Y′)OR¹⁶, —(CR¹⁹R²⁰)_(n)OC(═Y′)NR¹⁶R¹⁷,—(CR¹⁹R²⁰)_(n)OS(O)₂(OR¹⁶), —(CR¹⁹R²⁰)_(n)OP(═Y′)(OR¹⁶)(OR¹⁷),—(CR¹⁹R²⁰)_(n)OP(OR¹), —(CR¹⁹R²⁰)_(n)S(O)R¹⁶, —(CR¹⁹R²⁰)_(n)S(O)₂R¹⁶,—(CR¹⁹R²⁰)_(n)S(O)₂NR¹⁶R¹⁷, —(CR¹⁹R²⁰)_(n)S(O)(OR¹⁶),—(CR¹⁹R²⁰)_(n)S(O)₂(OR¹⁶), —(CR¹⁹R²⁰)_(n)SC(═Y′)R¹⁶,—(CR¹⁹R²⁰)_(n)SC(═Y′)OR¹⁶, —(CR¹⁹R²⁰)_(n)SC(═Y′)NR¹⁶R¹⁷, and R²¹; andall other variables are as defined in formula I, I-a or I-b, or asdefined in any one of the embodiments above.

In another embodiment of the present invention, X¹ is OR^(11′) whereinR^(11′) is heterocyclyl (e.g., 4- to 6-membered heterocyclyl) optionallysubstituted with one or more groups independently selected from halo,CN, CF₃, —OCF₃, —NO₂, oxo, —(CR¹⁹R²⁰)_(n)C(═Y′)R¹⁶,—(CR¹⁹R²⁰)_(n)C(═Y′)OR¹⁶, —(CR¹⁹R²⁰)_(n)C(═Y′)NR¹⁶R¹⁷,—(CR¹⁹R²⁰)_(n)NR¹⁶R¹⁷, —(CR¹⁹R²⁰)_(n)OR¹⁶, —(CR¹⁹R²⁰)_(n)SR¹⁶,—(CR¹⁹R²⁰)_(n)NR¹⁶C(═Y′)R¹⁷, —(CR¹⁹R²⁰)_(n)NR¹⁶C(═Y′)OR¹⁷,—(CR¹⁹R²⁰)_(n)NR¹⁸C(═Y′)NR¹⁶R¹⁷, —(CR¹⁹R²⁰)_(n)NR¹⁷SO₂R¹⁶,—(CR¹⁹R²⁰)_(n)OC(═Y′)R¹⁶, —(CR¹⁹R²⁰)_(n)OC(═Y′)OR¹⁶,—(CR¹⁹R²⁰)_(n)OC(═Y′)NR¹⁶R¹⁷, —(CR¹⁹R²⁰)_(n)OS(O)₂(OR¹⁶),—(CR¹⁹R²⁰)_(n)OP(═Y′)(OR¹⁶)(OR¹⁷), —(CR¹⁹R²⁰)_(n)OP(OR¹⁶)(OR¹⁷),—(CR¹⁹R²⁰)_(n)S(O)R¹⁶, —(CR¹⁹R²⁰)_(n)S(O)₂R¹⁶,—(CR¹⁹R²⁰)_(n)S(O)₂NR¹⁶R¹⁷, —(CR¹⁹R²⁰)_(n)S(O)(OR¹⁶),—(CR¹⁹R²⁰)_(n)S(O)₂(OR¹⁶), —(CR¹⁹R²⁰)_(n)SC(═Y′)R¹⁶,—(CR¹⁹R²⁰)_(n)SC(═Y′)OR¹⁶, —(CR¹⁹R²⁰)_(n)SC(═Y′)NR¹⁶R¹⁷, and R²¹; andall other variables are as defined in formula I, I-a or I-b, or asdefined in any one of the embodiments above.

In another embodiment of the present invention, X¹ is OR^(11′) whereinR^(11′) is 4- to 6-membered heterocyclyl having 1 nitrogen ring atomwherein said heterocyclyl is optionally substituted with one or moregroups independently selected from halo, CN, CF₃, —OCF₃, —NO₂, oxo,—(CR¹⁹R²⁰)_(n)C(═Y′)R¹⁶, —(CR¹⁹R²⁰)_(n)C(═Y′)OR¹⁶,—(CR¹⁹R²⁰)_(n)C(═Y′)NR¹⁶R¹⁷, —(CR¹⁹R²⁰)_(n)NR¹⁶R¹⁷, —(CR¹⁹R²⁰)_(n)OR¹⁶,—(CR¹⁹R²⁰)_(n)SR¹⁶, —(CR¹⁹R²⁰)_(n)NR¹⁶C(═Y′)R¹⁷,—(CR¹⁹R²⁰)_(n)NR¹⁶C(═Y′)OR¹⁷, —(CR¹⁹R²⁰)_(n)NR¹⁸C(═Y′)NR¹⁶R¹⁷,—(CR¹⁹R²⁰)_(n)NR¹⁷SO₂R¹⁶, —(CR¹⁹R²⁰)_(n)OC(═Y′)R¹⁶,—(CR¹⁹R²⁰)_(n)OC(═Y′)OR¹⁶, —(CR¹⁹R²⁰)_(n)OC(═Y)NR¹⁶R¹⁷,—(CR¹⁹R²⁰)_(n)OS(O)₂(OR¹⁶), —(CR¹⁹R²⁰)_(n)OP(═Y′)(OR¹⁶)(OR¹⁷),—(CR¹⁹R²⁰)_(n)OP(OR¹⁶)(OR¹⁷), —(CR¹⁹R²⁰)_(n)S(O)R¹⁶,—(CR¹⁹R²⁰)_(n)S(O)₂R¹⁶, —(CR¹⁹R²⁰)_(n)S(O)₂NR¹⁶R¹⁷,—(CR¹⁹R²⁰)_(n)S(O)(OR¹⁶), —(CR¹⁹R²⁰)_(n)S(O)₂(OR¹⁶),—(CR¹⁹R²⁰)_(n)SC(═Y′)R¹⁶, —(CR¹⁹R²⁰)_(n)SC(═Y′)OR¹⁶, —(CR¹⁹R²⁰)_(n)SC(═Y′)NR¹⁶R¹⁷, and R²¹; and all other variables are as defined informula I, I-a or I-b, or as defined in any one of the embodimentsabove.

In another embodiment of the present invention, X is:

and all other variables are as defined in formula I, I-a or I-b, or asdefined in any one of the embodiments above.

In another embodiment of the present invention, X¹ is

and all other variables are as defined in formula I, I-a or I-b, or asdefined in any one of the embodiments above.

In an embodiment of the present invention, X¹ is R^(11′); and all othervariables are as defined in formula I, I-a or I-b, or as defined in anyone of the embodiments above.

In another embodiment of the present invention, X¹ is R^(11′) whereinR^(11′) is H or C₁-C₁₂ alkyl (e.g., C₁-C₆ alkyl) substituted with one ormore groups independently selected from halo, CN, CF₃, —OCF₃, —NO₂, oxo,—Si(C₁-C₆ alkyl), —(CR¹⁹R²⁰)_(n)C(═Y′)R¹⁶, —(CR¹⁹R²⁰)_(n)C(═Y′)OR¹⁶,—(CR¹⁹R²⁰)_(n)C(═Y′)NR¹⁶R¹⁷, —(CR¹⁹R²⁰)_(n)NR¹⁶R¹⁷, —(CR¹⁹R²⁰)_(n)OR¹⁶,—(CR¹⁹R²⁰)_(n)SR¹⁶,—(CR¹⁹R²⁰)_(n)NR¹⁶C(═Y′)R¹⁷—(CR¹⁹R²⁰)_(n)NR¹⁶C(═Y′)OR¹⁷,—(CR¹⁹R²⁰)_(n)NR¹⁸C(═Y′)NR¹⁶R¹⁷, —(CR¹⁹R²⁰)_(n)NR¹⁷SO₂R¹⁶,—(CR¹⁹R²⁰)_(n)OC(═Y′)R¹⁶, —(CR¹⁹R²⁰)_(n)OC(═Y′)OR¹⁶,—(CR¹⁹R²⁰)_(n)OC(═Y′)NR¹⁶R¹⁷, —(CR¹⁹R²⁰)_(n)OS(O)₂(OR¹⁶),—(CR¹⁹R²⁰)_(n)OP(═Y′)(OR¹⁶)(OR¹⁷), —(CR¹⁹R²⁰)_(n)OP(OR¹⁶)(OR¹⁷),—(CR¹⁹R²⁰)_(n)S(O)R¹⁶, —(CR¹⁹R²⁰)_(n)S(O)₂R¹⁶,—(CR¹⁹R²⁰)_(n)S(O)₂NR¹⁶R¹⁷, —(CR¹⁹R²⁰)_(n)S(O)(OR¹⁶),—(CR¹⁹R²⁰)_(n)S(O)₂(OR¹⁶), —(CR¹⁹R²⁰)_(n)SC(═Y′)R¹⁶,—(CR¹⁹R²⁰)_(n)SC(═Y′)OR¹⁶, —(CR¹⁹R²⁰)_(n)SC(═Y′)NR¹⁶R¹⁷, and R²¹; andall other variables are as defined in formula I, I-a or I-b, or asdefined in any one of the embodiments above.

In another embodiment of the present invention, X¹ is

and all other variables are as defined in formula I, I-a or I-b, or asdefined in any one of the embodiments above.

In another embodiment of the present invention, R⁵ is H and X¹ is

and all other variables are as defined in formula I, I-a or I-b, or asdefined in any one of the embodiments above.

In another embodiment of the present invention, X¹ is

and all other variables are as defined in formula I, I-a or I-b, or asdefined in any one of the embodiments above.

In another embodiment of the present invention, R⁵ is methyl and X¹ is

and all other variables are as defined in formula I, I-a or I-b, or asdefined in any one of the embodiments above.

In an embodiment of the present invention, X¹ is R^(11′) and X¹ is takentogether with R⁵ and the nitrogen atom to which they are bound to form a4-5 membered saturated cyclic ring having 0-2 additional heteroatomsselected from O, S and N, wherein said cyclic ring is optionallysubstituted with one or more groups selected from halo, CN, CF₃, —OCF₃,—NO₂, oxo, —(CR¹⁹R²⁰)_(n)C(═Y′)R¹⁶, —(CR¹⁹R²⁰)_(n)C(═Y′)OR¹⁶,—(CR¹⁹R²⁰)_(n)C(═Y′)NR¹⁶R¹⁷, —(CR¹⁹R²⁰)_(n)NR¹⁶R¹⁷, —(CR¹⁹R²⁰)_(n)OR¹⁶,—(CR¹⁹R²⁰)_(n)—SR¹⁶, —(CR¹⁹R²⁰)_(n)NR¹⁶C(═Y′)R¹⁷,—(CR¹⁹R²⁰)_(n)NR¹⁶C(═Y′)OR¹⁷, —(CR¹⁹R²⁰)_(n)NR¹⁸C(═Y′)NR¹⁶R¹⁷,—(CR¹⁹R²⁰)_(n)NR¹⁷SO₂R¹⁶, —(CR¹⁹R²⁰)_(n)OC(═Y′)R¹⁶,—(CR¹⁹R²⁰)_(n)OC(═Y′)OR¹⁶, —(CR¹⁹R²⁰)_(n)OC(═Y′)NR¹⁶R¹⁷,—(CR¹⁹R²⁰)_(n)OS(O)₂(OR¹⁶), —(CR¹⁹R²⁰)_(n)OP(═Y′)(OR¹⁶)(OR¹⁷),—(CR¹⁹R²⁰)_(n)OP(OR¹⁶)(OR¹⁷), —(CR¹⁹R²⁰)_(n)S(O)R¹⁶,—(CR¹⁹R²⁰)_(n)S(O)₂R¹⁶, —(CR¹⁹R²⁰)_(n)S(O)₂NR¹⁶R¹⁷,—(CR¹⁹R²⁰)_(n)S(O)(OR¹⁶),—(CR¹⁹R²⁰)_(n)S(O)₂(OR¹⁶)—(CR¹⁹R²⁰)_(n)SC(═Y′)R¹⁶,—(CR¹⁹R²⁰)_(n)SC(═Y′)OR¹⁶, —(CR¹⁹R²⁰)_(n)SC(═Y′)NR¹⁶R¹⁷, and R²¹; andall other variables are as defined in formula I, I-a or I-b, or asdefined in any one of the embodiments above.

In another embodiment of the present invention, W is:

and all other variables are as defined in formula I, I-a or I-b, or asdefined in any one of the embodiments above.

In an embodiment of the present invention, W is —OR^(11′) whereinR^(11′) is H or C₁-C₁₂ alkyl; and all other variables are as defined informula I, I-a or I-b, or as defined in any one of the embodimentsabove.

In another embodiment of the present invention, W is —OR^(11′) whereinR^(11′) is H; and all other variables are as defined in formula I, I-aor I-b, or as defined in any one of the embodiments above.

In another embodiment of the present invention, W is —OR^(11′) whereinR^(11′) is C₁-C₆ alkyl; and all other variables are as defined informula I, I-a or I-b, or as defined in any one of the embodimentsabove.

In an embodiment of the present invention, W′ is NHSO₂R⁸; and all othervariables are as defined in formula I, I-a or I-b, or as defined in anyone of the embodiments above.

In an embodiment of the present invention, R⁶ is halo, C₂-C₈ alkynyl,carbocyclyl, or —SR¹⁶; and all other variables are as defined in formulaI, I-a or I-b, or as defined in any one of the embodiments above.

In another embodiment of the present invention, R⁶ is halo, C₂-C₃alkynyl, C₃-carbocyclyl, or —SR¹⁶ wherein R¹⁶ is C₁-C₂ alkyl; and allother variables are as defined in formula I, I-a or I-b, or as definedin any one of the embodiments above.

In an embodiment of the present invention, R^(6′) is H, halo, or C₁-C₃alkyl; and all other variables are as defined in formula I, I-a or I-b,or as defined in any one of the embodiments above.

In an embodiment of the present invention, p is 1 or 2; and all othervariables are as defined in formula I, I-a or I-b, or as defined in anyone of the embodiments above.

In another embodiment of the present invention, X⁴ is

and all other variables are as defined in formula I, I-a or I-b, or asdefined in any one of the embodiments above.

In another embodiment of the present invention, X⁴ is

and all other variables are as defined in formula I, I-a or I-b, or asdefined in any one of the embodiments above.

Another embodiment of the present invention includes compounds describedin EXAMPLES 5-25 and compounds below:

Preparation of Compounds of Formula I

The imidazopyridines of formula I are prepared according to theprocedures described below in the schemes and examples or by methodsknown in the art. For example, compounds of formula (I) where Y═W—C(O)—may be prepared according to Scheme 1.

Scheme 1

Nicotinic acids of formula (II) may be obtained commercially or preparedusing methods described in the literature. The acids (II) may be reactedwith anilines (incorporating appropriate substituents R1), in thepresence of a base such as LiHMDS, in a solvent such as THF, at atemperature of from −78° C. to 25° C. to give acids of formula (III).Nicotinic esters (IV) may be prepared from nicotinic acids (III) byreaction with an alkylating agent such as trimethylsilyl diazomethane ina solvent such as toluene, at a temperature of from 0° C. to 50° C.2-Anilino-6-cyanopyridines of formula (V) may be prepared from 6-halopyridines (IV) by reaction with an inorganic cyanide such as zinccyanide, in the presence of a transition metal catalyst such asPd(PPh₃)₄, in a solvent such as DMF, at a temperature of from 50° C. toreflux temperature, or under microwave irradiation at a temperature offrom 70° C. to 200° C. Cyanopyridines (V) may be reduced to give2-aminomethylpyridines (VI), A=CH₂, by reduction with hydrogen at apressure of from 1 to 5 atmospheres, in the presence of a catalyst suchas palladium on carbon, in a solvent such as methanol or acetic acid,with or without added strong acid such as concentrated hydrochloricacid. Alternatively, the cyanopyridines (V) may be converted to2-aminomethylpyridines by reacting with an inorganic metal hydride suchas sodium borohydride, in the presence of a metal salt such as cobaltchloride, in a solvent such as methanol, at a temperature of from 0° C.to room temperature. Alternatively compounds of formula (VI), A=NH, maybe prepared from compounds of formula (IV) by reaction with hydrazinehydrate, in a solvent such as ethanol, at a temperature of from 0° C. toreflux.

Compounds (VII) may be prepared from compounds (VI) by reaction with ananhydride such as acetic anhydride, or mixed anhydride such asformic-acetic anhydride, in a solvent such as tetrahydrofuran, at atemperature of from 0° C. to reflux. Compounds of formula (VIII) may beprepared from compounds (VII) by reaction with a chlorinating agent suchas phosphorous oxychloride, in a solvent such as toluene, at atemperature of from 25° C. to reflux. Alternatively compounds of formula(VIII) may be prepared from compounds of formula (VII) by reaction withan acid such as formic acid, neat or in a solvent such as dioxane, at atemperature of from 50° C. to reflux. Compounds of formula (IX) can beobtained from compounds of formula (VIII) by reaction with a base suchas sodium hydroxide, in a solvent such as ethanol or methanol, at atemperature of from room temperature up to reflux temperature.

Compounds of formula (IX) can be reacted with a functionalisedhydroxylamine of formula (XII) (commercially available or preparedaccording to Scheme 5, 6 and 7) or an amine, and a suitable couplingagent, such asO-(7-aza-benzo-triazol-1-yl)-N,N,N′,N′-tetra-methyluroniumhexafluoro-phosphate, N-(3-dimethylaminopropyl)-N′-ethylcarbodiimidehydrochloride or N,N′-dicyclohexylcarbodiimide in the presence ofN-hydroxy-1,2,3-benzotriazole, in the presence of a suitable base suchas diisopropylethylamine or triethylamine in an inert solvent, such astetrahydrofuran, N,N-dimethylformamide, or dichloromethane at atemperature of about room temperature, to obtain the compounds offormula (X). Compounds of formula (X) can be obtained directly fromcompounds of formula (VIII) by reaction with an amine or hydroxylamineDNHR in the presence of a Lewis acid such as trimethyl aluminium, in asolvent such as DCM, at a temperature of from room temperature up toreflux temperature. Alternatively, compounds of formula (X) may beprepared from compounds of formula (VIII) by treatment with afunctionalized hydroxylamine in the presence of a base such as lithiumbis(trimethylsilyl)amide in a solvent such as THF at a temperature offrom −78° C. to 25° C.

Additionally, compounds of formula (I) where Y is W—C(O)— may beprepared according to Scheme 2.

Compounds of formula (XV) may be obtained commercially or prepared usingmethods described in the literature. Compounds of formula (XVI) may beprepared from compounds of formula (XV) by reaction with a halogenatingagent such as N-bromo succinimide or 1,3-dibromo-5,5-dimethylhydantoinin the presence of a catalyst such as AIBN or benzoyl peroxide in asolvent such as dichloroethane or carbon tetrachloride using activationby light or heat at a temperature of from room temperature to reflux.Alternatively, compounds of formula (XVI) may be obtained from compoundsof formula (XV) in a two step procedure by first formation of thepyridine N-oxide using an oxidizing agent such as 3-chloro-peroxybenzoic acid in a solvent such as DCM at a temperature of about roomtemperature. The intermediate N-oxides may be converted tohalomethylpyridines of formula (XVI) by reaction with a chlorinatingagent such as phosphorous oxychloride. Compounds of formula (XVII) maybe prepared from compounds of formula (XVI) by reaction with a protectedform of ammonia such as potassium phthalimide or sodium diformyl imidein a solvent such as DMF at a temperature of from −5° C. to 50° C. WhenR′″═H and R″″═C(═O)H compounds of formula (XVII) may be converted toformyl amino nicotinic esters of formula (XVIII) by treatment with anacid such as formic acid or hydrochloric acid in a solvent such asmethanol at a temperature of from room temperature to reflux. Compoundsof formula (XVIII) may be cyclised to imidazopyridines of formula (XIX)by reaction with a phosphorous oxyhalide such as phosphorous oxychloridein a solvent such as toluene at a temperature of from 50° C. to reflux.Alternatively, the cyclisation maybe effected using an acid such asformic acid or acetic acid, neat, at a temperature of from 25° C. toreflux. Imidazopyridine-5-anilino esters of formula (XX) may be preparedfrom halides of formula (XIX) by reaction with an aniline (incorporatingappropriate substituents R1), in the presence of a base such as lithiumbis(trimethylsilyl)amide in a solvent such as THF at a temperature offrom −78° C. to room temperature. Alternatively, compounds of formula(XX) may be prepared from compounds of formula (XIX) by reaction with ananiline (incorporating appropriate substituents R1), in the presence ofa catalyst such as tris(dibenzylideneacetone)dipalladium (0), a basesuch as potassium phosphate, a ligand such as2-dicyclohexylphosphino-2′,6′-(diisopropoxy)biphenyl, in a suitablesolvent such as toluene, at a temperature of from room temperature tothe reflux temperature of the solvent, or under microwave irradiation ata temperature of from 70° C. to 150° C. Acids of formula (XXI) may beprepared from esters of formula (XX) using the methods described for theconversion of compounds of formula (VIII) to compounds of formula (IX)in Scheme 1. Alternatively, acids of formula (XXI) may be prepared fromcompounds of formula (XIX) first by saponification using the methodsdescribed for the conversion of compounds of formula (VIII) to compoundsof formula (IX) followed by treatment with an aniline (incorporatingappropriate substituents R1), in the presence of a base such as lithium(bistrimethylsilyl)amide in a solvent such as THF at a temperature offrom −78° C. to room temperature.

Anilino acids of formula (XXI) may be converted to compounds of formula(X) using the methods described for the conversion of compounds offormula (IX) to compounds of formula (X) in Scheme 1. In addition,esters of formula (XX) may be converted to compounds of formula (X)using the methods described for the conversion of compounds of formula(VIII) to compounds of formula (X) in Scheme 1.

Compounds of formula (XVI) and (XVII) may be prepared according toScheme 3.

Compounds of formula (XXIII) may be prepared from compounds of formula(XXII). Compounds of formula (XXII) are first esterified by formation ofthe bis-acid chloride using oxalyl chloride with catalytic DMF, in asolvent such as DCM, at a temperature of about room temperature followedby quench with an alcohol such as methanol. The resultant bis-esterintermediate may then be oxidized to compounds of formula (XXIII) byreaction with an oxidizing agent such as meta-chloro peroxybenzoic acidin a solvent such as DCM at a temperature of from 0° C. to roomtemperature. Compounds of formula (XXV) may be prepared from compoundsof formula (XXIV) by reduction with a metal hydride such as sodiumborohydride in the presence of an additive such as calcium chloride, ina solvent such as ethanol, at a temperature of from 0° C. to roomtemperature. Compounds of formula (XXV) may be converted to compounds offormula (XXVI) where R═Cl by halogenation using a sulfonyl chloride suchas thionyl chloride in a solvent such as dichloromethane, at atemperature of from −5° C. to room temperature. Compounds of formula(XXVI) where R═N₃ may be obtained from compounds of formula (XXV) byreaction with an azide such as diphenyl phosphoryl azide, in thepresence of a diazocarboxylate such as diisopropyl azodicarboxylate, inthe presence of a base such as triethylamine, in a solvent such as THFat a temperature of about room temperature. Compounds of formula (XXVI)where R═N₃ may be converted to compounds of formula (XXVI) where R═NH₂by treatment with a reducing agent such as triphenyl phosphine in asolvent such as THF at a temperature of from room temperature to reflux.

Compounds of formula (I) where Y is R⁸SO₂NH— may be prepared accordingto Scheme 4.

Compounds of formula (XXVII) may be prepared from compounds of formula(IX) by treatment with diphenylphosphoryl azide in a solvent such astoluene, in the presence of a base such as triethylamine. Compounds offormula (XXVIII) may be prepared from compounds of formula (XXVII) bytreatment with a base such as sodium hydride, in a solvent such as DMF,followed by reaction with a sulfonyl chloride (appropriatelysubstituted). Compounds of formula (XXIX) may be prepared from compoundsof formula (XXVIII) by deprotection using a base such as sodiumhydroxide, in a solvent such as DMF, at a temperature of from 50° C. to150° C.

Hydroxylamines of formula (XII) may be prepared using methods describedin the literature or the synthetic route outlined in Scheme 5.

Primary or secondary alcohols of general formula (XXXVII) may beprepared using methods described in the literature. The alcohols may bereacted with N-hydroxy phthalimide using a phosphine and couplingreagent such as diethyl azodicarboxylate to provide compounds of generalformula (XXXVIII). Compounds of general formula (XXXVIII) may bedeprotected using hydrazine, methyl hydrazine, an acid such ashydrochloric acid or a base such as aqueous ammonia to providehydroxylamines of general formula (XII-a).

Compounds of formula (XII-a) may be further modified by reductiveamination with aldehydes or ketones using a reducing agent such assodium triacetoxy borohydride, sodium cyanoborohydride, orborane-pyridine in a solvent such as dichloroethane at a temperature offrom ambient temperature to reflux to provide hydroxylamines of generalformula (XII-b). In addition, compounds of formula (XII-a) may befurther modified by alkylation with an alkyl halide in the presence of abase such as triethylamine, in a solvent such as dichloromethane, toprovide hydroxylamines of general formula (XII-b).

Alternatively, hydroxylamines of formula (XII-a) may be preparedaccording to Scheme 6.

Alkyl halides of formula (XL) may be reacted with N-hydroxy phthalimidein the presence of a base such as potassium carbonate in a solvent suchas dimethyl sulfoxide at a temperature of from 10° C. to 50° C.Compounds of formula (XLI) may be converted to compounds of formula(XII) using the methods described for the conversion of compounds offormula (XXXVIII) to compounds of formula (XII) in Scheme 5.

Alternatively, compounds of formula (XII-a) may be prepared according toScheme 7.

Compounds of formula (XLII) may be reacted with N-hydroxy phthalimide inthe presence of a catalytic amount of a base such as DIPEA and aco-catalyst such as tetra-butyl ammonium bromide in a solvent such astoluene at a temperature of form 50° C. to reflux. Compounds of formula(XLIII) may be converted to compounds of formula (XII) using the methodsdescribed for the conversion of compounds of formula (XXXVIII) tocompounds of formula (XII) in Scheme 5.

Anilines of general formula (XXXI) used in condensations andcross-coupling reactions described above may be prepared by usingmethods described in the literature or according to Scheme 8.

Substituted 1-chloro-4-nitro benzene may be reacted with a metal R′″MXn,such as cyclopropyl boronic acid or hexamethyldisilazane, in a solventsuch as xylene, using a catalyst such astetrakis(triphenylphosphine)palladium, at a temperature of from roomtemperature to reflux to give compounds of formula (XXX). The nitrogroup may be reduced using methods described in the literature such asreaction under an atmosphere of hydrogen, at a pressure of from 1 to 5atmospheres, in the presence of a catalyst such as palladium on carbon,and in a solvent such as ethanol or ethyl acetate, at room temperatureto give compounds of formula (XXXI).

Alternatively, anilines of formula (LV) may be prepared according toScheme 9.

4-Bromo or iodo anilines of formula (LIV) may be reacted with at least 2equivalents of a strong organometallic base such as n-butyliithium in asolvent such as THF at a temperature of from −100° C. to −20° C.followed by quench of the intermediate aryl lithium species with anelectrophile such as trimethyl silyl chloride to give compounds offormula (LV).

It will be appreciated that where appropriate functional groups exist,compounds of formula (I) or any intermediates used in their preparationmay be further derivatised by one or more standard synthetic methodsemploying substitution, oxidation, reduction, or cleavage reactions.Particular substitution approaches include conventional alkylation,arylation, heteroarylation, acylation, sulfonylation, halogenation,nitration, formylation and coupling procedures.

For example, aryl bromide or chloride groups may be converted to aryliodides using a Finkelstein reaction employing an iodide source such assodium iodide, a catalyst such as copper iodide and a ligand such astrans-N,N-dimethyl-1,2-cyclohexane diamine in a solvent such as1,4-dioxane and heating the reaction mixture at reflux temperature. Aryltrialkylsilanes may be converted to aryl iodides by treating the silanewith an iodide source such as iodine monochloride in a solvent such asdichloromethane with or without Lewis acid such as silvertetrafluoroborate at a temperature from −40° C. to reflux.

In a further example primary amine (—NH₂) groups may be alkylated usinga reductive alkylation process employing an aldehyde or a ketone and aborohydride, for example sodium triacetoxyborohydride or sodiumcyanoborohydride, in a solvent such as a halogenated hydrocarbon, forexample 1,2-dichloroethane, or an alcohol such as ethanol, wherenecessary in the presence of an acid such as acetic acid at aroundambient temperature. Secondary amine (—NH—) groups may be similarlyalkylated employing an aldehyde.

In a further example, primary amine or secondary amine groups may beconverted into amide groups (—NHCOR′ or NRCOR′) by acylation. Acylationmay be achieved by reaction with an appropriate acid chloride in thepresence of a base, such as triethylamine, in a suitable solvent, suchas dichloromethane, or by reaction with an appropriate carboxylic acidin the presence of a suitable coupling agent such HATU(O-(7-azabenzotriazol-1-ye-N,N,N′,N′-tetramethyluroniumhexafluorophosphate) in a suitable solvent such as dichloromethane.Similarly, amine groups may be converted into sulfonamide groups(—NHSO₂R′ or NR″SO₂R′) by reaction with an appropriate sulfonyl chloridein the presence of a suitable base, such as triethylamine, in a suitablesolvent such as dichloromethane. Primary or secondary amine groups canbe converted into urea groups (—NHCONR′R″ or NRCONR′R″) by reaction withan appropriate isocyanate in the presence of a suitable base such astriethylamine, in a suitable solvent, such as dichloromethane.

An amine (—NH₂) may be obtained by reduction of a nitro (—NO₂) group,for example by catalytic hydrogenation, using for example hydrogen inthe presence of a metal catalyst, for example palladium on a supportsuch as carbon in a solvent such as ethyl acetate or an alcohol e.g.methanol. Alternatively, the transformation may be carried out bychemical reduction using for example a metal, e.g. tin or iron, in thepresence of an acid such as hydrochloric acid.

In a further example, amine (—CH₂NH₂) groups may be obtained byreduction of nitriles (—CN), for example by catalytic hydrogenationusing for example hydrogen in the presence of a metal catalyst, forexample palladium on a support such as carbon, or Raney nickel, in asolvent such as an ether e.g. a cyclic ether such as tetrahydrofuran, ata temperature from 78° C. to the reflux temperature of the solvent.

In a further example, amine (—NH₂) groups may be obtained fromcarboxylic acid groups (—CO₂H) by conversion to the corresponding acylazide (—CON₃), Curtius rearrangement and hydrolysis of the resultantisocyanate (—N═C═O).

Aldehyde groups (—CHO) may be converted to amine groups (—CH₂NR′R″)) byreductive amination employing an amine and a borohydride, for examplesodium triacetoxyborohydride or sodium cyanoborohydride, in a solventsuch as a halogenated hydrocarbon, for example dichloromethane, or analcohol such as ethanol, where necessary in the presence of an acid suchas acetic acid at around ambient temperature.

In a further example, aldehyde groups may be converted into alkenylgroups (—CH═CHR′) by the use of a Wittig or Wadsworth-Emmons reactionusing an appropriate phosphorane or phosphonate under standardconditions known to those skilled in the art.

Aldehyde groups may be obtained by reduction of ester groups (such as—CO₂Et) or nitriles (—CN) using diisobutylaluminium hydride in asuitable solvent such as toluene. Alternatively, aldehyde groups may beobtained by the oxidation of alcohol groups using any suitable oxidisingagent known to those skilled in the art.

Ester groups (—CO₂R′) may be converted into the corresponding acid group(—CO₂H) by acid- or base-catalused hydrolysis, depending on the natureof R. If R is t-butyl, acid-catalysed hydrolysis can be achieved forexample by treatment with an organic acid such as trifluoroacetic acidin an aqueous solvent, or by treatment with an inorganic acid such ashydrochloric acid in an aqueous solvent.

Carboxylic acid groups (—CO₂H) may be converted into amides (CONHR′ orCONR′R″) by reaction with an appropriate amine in the presence of asuitable coupling agent, such as HATU, in a suitable solvent such asdichloromethane.

In a further example, carboxylic acids may be homologated by one carbon(i.e CO₂H to CH₂CO₂H) by conversion to the corresponding acid chloride(—COCl) followed by Arndt-Eistert synthesis.

In a further example, —OH groups may be generated from the correspondingester (e.g. —CO₂R′), or aldehyde (—CHO) by reduction, using for examplea complex metal hydride such as lithium aluminium hydride in diethylether or tetrahydrofuran, or sodium borohydride in a solvent such asmethanol. Alternatively, an alcohol may be prepared by reduction of thecorresponding acid (—CO₂H), using for example lithium aluminium hydridein a solvent such as tetrahydrofuran, or by using borane in a solventsuch as tetrahydrofuran.

Alcohol groups may be converted into leaving groups, such as halogenatoms or sulfonyloxy groups such as an alkylsulfonyloxy, e.g.trifluoromethylsulfonyloxy or arylsulfonyloxy, e.g. p-toluenesulfonyloxygroup using conditions known to those skilled in the art. For example,an alcohol may be reacted with thioyl chloride in a halogenatedhydrocarbon (e.g. dichloromethane) to yield the corresponding chloride.A base (e.g. triethylamine) may also be used in the reaction.

In another example, alcohol, phenol or amide groups may be alkylated bycoupling a phenol or amide with an alcohol in a solvent such astetrahydrofuran in the presence of a phosphine, e.g. triphenylphosphineand an activator such as diethyl-, diisopropyl, ordimethylazodicarboxylate. Alternatively alkylation may be achieved bydeprotonation using a suitable base e.g. sodium hydride followed bysubsequent addition of an alkylating agent, such as an alkyl halide.

Aromatic halogen substituents in the compounds may be subjected tohalogen-metal exchange by treatment with a base, for example a lithiumbase such as n-butyl or t-butyl lithium, optionally at a lowtemperature, e.g. around −78° C., in a solvent such as tetrahydrofuran,and then quenched with an electrophile to introduce a desiredsubstituent. Thus, for example, a formyl group may be introduced byusing N,N-dimethylformamide as the electrophile. Aromatic halogensubstituents may alternatively be subjected to metal (e.g. palladium orcopper) catalysed reactions, to introduce, for example, acid, ester,cyano, amide, aryl, heteraryl, alkenyl, alkynyl, thio- or aminosubstituents. Suitable procedures which may be employed include thosedescribed by Heck, Suzuki, Stille, Buchwald or Hartwig.

Aromatic halogen substituents may also undergo nucleophilic displacementfollowing reaction with an appropriate nucleophile such as an amine oran alcohol. Advantageously, such a reaction may be carried out atelevated temperature in the presence of microwave irradiation.

The compounds of the present invention are tested for their capacity toinhibit MEK activity and activation (primary assays) and for theirbiological effects on growing cells (secondary assays) as describedbelow. The compounds of the present invention having IC₅₀ of less than 5μM (more preferably less than 0.1 μM, most preferably less than 0.01 μM)in the MEK activity assay of Example 1, IC₅₀ of less than 5 (morepreferably less than 1 μM, even more preferably less than 0.1 μM, mostpreferably less than 0.01 μM) in the MEK activation assay of Example 2,EC₅₀ of less than 10 μM (more preferably less than 1 μM, even morepreferably less than 0.5 μM, most preferably less than 0.1 μM) in thecell proliferation assay of Example 3, and/or EC₅₀ of less than 10 μM(more preferably less than 1 μM, even more preferably less than 0.5 mostpreferably less than 0.1 μM) in the ERK phosphorylation assay of Example4, are useful as MEK inhibitors.

The present invention includes a composition (e.g., a pharmaceuticalcomposition) comprising a compound of formula I (and/or solvates and/orsalts thereof) and a carrier (a pharmaceutically acceptable carrier).The present invention also includes a composition (e.g., apharmaceutical composition) comprising a compound of formula I (and/orsolvates and/or salts thereof) and a carrier (a pharmaceuticallyacceptable carrier), further comprising a second chemotherapeutic and/ora second anti-inflammatory agent such as those described herein. Thepresent compositions are useful for inhibiting abnormal cell growth ortreating a hyperproliferative disorder in a mammal (e.g., human). Thepresent compositions are also useful for treating inflammatory diseasesin a mammal (e.g., human).

The present compounds (such as any one of the title compounds ofEXAMPLES 5-25) and compositions are also useful for treating anautoimmune disease, destructive bone disorder, proliferative disorders,infectious disease, viral disease, fibrotic disease or neurodegenerativedisease in a mammal (e.g., human). Examples of such diseases/disordersinclude, but are not limited to, diabetes and diabetic complications,diabetic retinopathy, retinopathy of prematurity, age-related maculardegeneration, hemangioma, idiopathic pulmonary fibrosis, rhinitis andatopic dermatitis, renal disease and renal failure, polycystic kidneydisease, congestive heart failure, neurofibromatosis, organ transplantrejection, cachexia, stroke, septic shock, heart failure, organtransplant rejection, Alzheimer's disease, chronic or neuropathic pain,and viral infections such as HIV, hepatitis (B) virus (HBV), humanpapilloma virus (HPV), cytomegalovirus (CMV), and Epstein-Barr virus(EBV). Chronic pain, for purposes of the present invention includes, butis not limited to, idiopathic pain, and pain associated with chronicalcoholism, vitamin deficiency, uremia, hypothyroidism, inflammation,arthritis, and post-operative pain. Neuropathic pain is associated withnumerous conditions which include, but are not limited to, inflammation,postoperative pain, phantom limb pain, burn pain, gout, trigeminalneuralgia, acute herpetic and postherpetic pain, causalgia, diabeticneuropathy, plexus avulsion, neuroma, vasculitis, viral infection, crushinjury, constriction injury, tissue injury, limb amputation, arthritispain, and nerve injury between the peripheral nervous system and thecentral nervous system.

The present compounds (such as any one of the title compounds ofEXAMPLES 5-25) and compositions are also useful for treatingpancreatitis or kidney disease (including proliferativeglomerulonephritis and diabetes-induced renal disease) in a mammal(e.g., human).

The present compounds (such as any one of the title compounds ofEXAMPLES 5-25) and compositions are also useful for the prevention ofblastocyte implantation in a mammal (e.g., human).

The present invention includes a method of inhibiting abnormal cellgrowth or treating a hyperproliferative disorder in a mammal (e.g.,human) comprising administering to said mammal a therapeuticallyeffective amount of a compound of formula I (and/or solvates and/orsalts thereof) or a composition thereof. Also included in the presentinvention is a method of treating an inflammatory disease in a mammal(e.g., human) comprising administering to said mammal a therapeuticallyeffective amount of a compound of formula I (and/or solvates and/orsalts thereof) or a composition thereof.

The present invention includes a method of inhibiting abnormal cellgrowth or treating a hyperproliferative disorder in a mammal (e.g.,human) comprising administering to said mammal a therapeuticallyeffective amount of a compound of formula I (and/or solvates and/orsalts thereof) or a composition thereof, in combination with a secondchemotherapeutic agent such as those described herein. The presentinvention also includes a method of treating an inflammatory disease ina mammal (e.g., human) comprising administering to said mammal atherapeutically effective amount of a compound of formula I (and/orsolvates and/or salts thereof) or a composition thereof, in combinationwith a second anti-inflammatory agent such as those described herein.

The present invention includes a method of treating an autoimmunedisease, destructive bone disorder, proliferative disorders, infectiousdisease, viral disease, fibrotic disease or neurodegenerative disease ina mammal (e.g., human) comprising administering to said mammal atherapeutically effective amount of a compound of formula I (and/orsolvates and salts thereof) or a composition thereof, and optionallyfurther comprising a second therapeutic agent. Examples of suchdiseases/disorders include, but are not limited to, diabetes anddiabetic complications, diabetic retinopathy, retinopathy ofprematurity, age-related macular degeneration, hemangioma, idiopathicpulmonary fibrosis, rhinitis and atopic dermatitis, renal disease andrenal failure, polycystic kidney disease, congestive heart failure,neurofibromatosis, organ transplant rejection, cachexia, stroke, septicshock, heart failure, organ transplant rejection, Alzheimer's disease,chronic or neuropathic pain, and viral infections such as HIV, hepatitis(B) virus (HBV), human papilloma virus (HPV), cytomegalovirus (CMV), andEpstein-Barr virus (EBV).

The present invention includes a method of treating pancreatitis orkidney disease (including proliferative glomerulonephritis anddiabetes-induced renal disease) in a mammal (e.g., human) comprisingadministering to said mammal a therapeutically effective amount of acompound of formula I (and/or solvates and salts thereof) or acomposition thereof, and optionally further comprising a secondtherapeutic agent.

The present invention includes a method for preventing of blastocyteimplantation in a mammal (e.g., human) comprising administering to saidmammal a therapeutically effective amount of a compound of formula I(and/or solvates and salts thereof) or a composition thereof, andoptionally further comprising a second therapeutic agent.

The present invention includes a method of using the present compoundsfor in vitro, in situ, and in vivo diagnosis or treatment of mammaliancells, organisms, or associated pathological conditions.

It is also believed that the compounds of the present invention canrender abnormal cells more sensitive to treatment with radiation forpurposes of killing and/or inhibiting the growth of such cells.Accordingly, this invention further relates to a method for sensitizingabnormal cells in a mammal (e.g., human) to treatment with radiationwhich comprises administering to said mammal an amount of a compound offormula I (and/or solvates and salts thereof) or a composition thereof,which amount is effective is sensitizing abnormal cells to treatmentwith radiation.

Administration of the compounds of the present invention (hereinafterthe “active compound(s)”) can be effected by any method that enablesdelivery of the compounds to the site of action. These methods includeoral routes, intraduodenal routes, parenteral injection (includingintravenous, subcutaneous, intramuscular, intravascular or infusion),topical, inhalation and rectal administration.

The amount of the active compound administered will be dependent on thesubject being treated, the severity of the disorder or condition, therate of administration, the disposition of the compound and thediscretion of the prescribing physician. However, an effective dosage isin the range of about 0.001 to about 100 mg per kg body weight per day,preferably about 1 to about 35 mg/kg/day, in single or divided doses.For a 70 kg human, this would amount to about 0.05 to 7 g/day,preferably about 0.05 to about 2.5 g/day. In some instances, dosagelevels below the lower limit of the aforesaid range may be more thanadequate, while in other cases still larger doses may be employedwithout causing any harmful side effect, provided that such larger dosesare first divided into several small doses for administration throughoutthe day.

The active compound may be applied as a sole therapy or in combinationwith one or more chemotherapeutic or anti-inflammatory agents, forexample those described herein. Such conjoint treatment may be achievedby way of the simultaneous, sequential or separate dosing of theindividual components of treatment.

The pharmaceutical composition may, for example, be in a form suitablefor oral administration as a tablet, capsule, pill, powder, sustainedrelease formulations, solution, suspension, for parenteral injection asa sterile solution, suspension or emulsion, for topical administrationas an ointment or cream or for rectal administration as a suppository.The pharmaceutical composition may be in unit dosage forms suitable forsingle administration of precise dosages. The pharmaceutical compositionwill include a conventional pharmaceutical carrier or excipient and acompound according to the invention as an active ingredient. Inaddition, it may include other medicinal or pharmaceutical agents,carriers, adjuvants, etc.

Exemplary parenteral administration forms include solutions orsuspensions of active compounds in sterile aqueous solutions, forexample, aqueous propylene glycol or dextrose solutions. Such dosageforms can be suitably buffered, if desired.

Suitable pharmaceutical carriers include inert diluents or fillers,water and various organic solvents. The pharmaceutical compositions may,if desired, contain additional ingredients such as flavorings, binders,excipients and the like. Thus for oral administration, tabletscontaining various excipients, such as citric acid may be employedtogether with various disintegrants such as starch, alginic acid andcertain complex silicates and with binding agents such as sucrose,gelatin and acacia. Additionally, lubricating agents such as magnesiumstearate, sodium lauryl sulfate and talc are often useful for tabletingpurposes. Solid compositions of a similar type may also be employed insoft and hard filled gelatin capsules. Preferred materials, therefore,include lactose or milk sugar and high molecular weight polyethyleneglycols. When aqueous suspensions or elixirs are desired for oraladministration the active compound therein may be combined with varioussweetening or flavoring agents, coloring matters or dyes and, ifdesired, emulsifying agents or suspending agents, together with diluentssuch as water, ethanol, propylene glycol, glycerin, or combinationsthereof.

Methods of preparing various pharmaceutical compositions with a specificamount of active compound are known, or will be apparent, to thoseskilled in this art. For examples, see Remington's PharmaceuticalSciences, Mack Publishing Company, Ester, Pa., 15.sup.th Edition (1975).

EXAMPLES

Abbreviations nBuLi n-Butyllithium CDCl₃ Deuterated chloroform CD₃ODDeuterated methanol CH₂Cl₂ Dichloromethane DCM Dichloromethane DIPEADiisopropylethylamine DMF Dimethylformamide DMSO Dimethylsulfoxide Dppf1,1′-Bis(diphenylphosphino)ferrocene EDCI1-Ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride Et₃NTriethylamine Et₂O Diethyl ether HATUO-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate HCl Hydrochloric acid HMN Diatomaceous earth HOBt1-Hydroxybenzotriazole H₂SO₄ Sulfuric acid ICl Iodine monochloride IMSIndustrial methylated spirits LHMDS Lithium bis(trimethylsilyl)amideMeOH Methanol MgSO₄ Magnesium sulfate NaHCO₃ Sodium hydrogen carbonateNa₂SO₄ Sodium sulfate NBS N-Bromosuccinimide Pd(PPh₃)₄Tetrakis(triphenylphosphine)palladium(0) Pd₂dba₃Tris-(dibenzylideneacetone)dipalladium(0) Pd(dppf)Cl₂[1,1′-Bis(diphenylphosphino)ferrocene]dichloro- palladium(II) Si-PPCPre-packed silica flash chromatography cartridge: Isolute ® SPE, BiotageSNAP ® or ISCO Redisep ® SCX-2 Isolute ® silica-based sorbent with achemically bonded propylsulfonic acid functional group. THFTetrahydrofuran

General Experimental Conditions

¹H NMR spectra were recorded at ambient temperature using a Varian UnityInova (400 MHz) spectrometer with a triple resonance 5 mm probe.Chemical shifts are expressed in ppm relative to tetramethylsilane. Thefollowing abbreviations have been used: br=broad signal, s=singlet,d=doublet, dd=double doublet, t=triplet, q=quartet, m=multiplet.

High Pressure Liquid Chromatography—Mass Spectrometry (LCMS) experimentsto determine retention times (R_(T)) and associated mass ions wereperformed using one of the following methods.

Method A: Experiments performed on a Waters Micromass ZQ quadrupole massspectrometer linked to a Hewlett Packard HP 1100 LC system with diodearray detector. This system uses a Higgins Clipeus 5 micron C18 100×3.0mm column and a 1 ml/minute flow rate. The initial solvent system was95% water containing 0.1% formic acid (solvent A) and 5% acetonitrilecontaining 0.1% formic acid (solvent B) for the first minute followed bya gradient up to 5% solvent A and 95% solvent B over the next 14minutes. The final solvent system was held constant for a further 5minutes.

Method B: Experiments performed on a Waters Platform LC quadrupole massspectrometer linked to a Hewlett Packard HP1100 LC system with diodearray detector and 100 position autosampler using a Phenomenex LunaC18(2) 30×4.6 mm column and a 2 ml/minute flow rate. The solvent systemwas 95% water containing 0.1% formic acid (solvent A) and 5%acetonitrile containing 0.1% formic acid (solvent B) for the first 0.50minutes followed by a gradient up to 5% solvent A and 95% solvent B overthe next 4 minutes. The final solvent system was held constant for afurther 0.50 minutes.

Method C: Experiments performed on a PE Sciex API 150 EX quadrupole massspectrometer linked to a Shimadzu LC-10AD LC system with diode arraydetector and 225 position autosampler using a Kromasil C18 50×4.6 mmcolumn and a 3 ml/minute flow rate. The solvent system was a gradientstarting with 100% water with 0.05% TFA (solvent A) and 0% acetonitrilewith 0.0375% TFA (solvent B), ramping up to 10% solvent A and 90%solvent B over 4 minutes. The final solvent system was held constant fora further 0.50 minutes.

Method D: Experiments performed on an Agilent Technologies liquidchromatography mass spectrometer linked to an Agilent TechnologiesSeries 1200 LC system with diode array detector using a Zorbax 1.8micron SB-C18 30×2.1 mm column with a 1.5 ml/minute flow rate. MethodD1: The initial solvent system was 95% water containing 0.05%trifluoroacetic acid (solvent A) and 5% acetonitrile containing 0.05%trifluoroacetic acid (solvent B), followed by a gradient up to 5%solvent A and 95% solvent B over 1.5 minutes. The final solvent systemwas held constant for a further 1 minute. Method D2: The initial solventsystem was 95% water containing 0.05% trifluoroacetic acid (solvent A)and 5% acetonitrile containing 0.05% trifluoroacetic acid (solvent B),followed by a gradient up to 5% solvent A and 95% solvent B over 3.0minutes. The final solvent system was held constant for a further 1minute.

Method E: Experiments performed on an Agilent Technologies liquidchromatography mass spectrometer linked to an Agilent TechnologiesSeries 1200 LC system with diode array detector using a Zorbax 1.8micron SB-C18 30×2.1 mm column with a 0.6 ml/minute flow rate. MethodE1: The initial solvent system was 95% water containing 0.05%trifluoroacetic acid (solvent A) and 5% acetonitrile containing 0.05%trifluoroacetic acid (solvent B), followed by a gradient up to 5%solvent A and 95% solvent B over 9.0 minutes. The final solvent systemwas held constant for a further 1 minute. Method E2: The initial solventsystem was 95% water containing 0.05% trifluoroacetic acid (solvent A)and 5% acetonitrile containing 0.05% trifluoroacetic acid (solvent B),followed by a gradient up to 5% solvent A and 95% solvent B over 20.0minutes. The final solvent system was held constant for a further 1minute.

Microwave experiments were carried out using a Personal Chemistry ErnrysIniatiator™ or Optimizer™, which uses a single-mode resonator anddynamic field tuning, both of which give reproducibility and control.Temperature from 40-250° C. can be achieved, and pressures of up to 20bar can be reached.

Example 1 MEK Assay (MEK Activity Assay)

Constitutively activated human mutant MEK1 expressed in insect cells isused as source of enzymatic activity at a final concentration in thekinase assay of 15 nM.

The assay is carried out for 30 minutes in the presence of 50 μM ATPusing recombinant GST-ERK1 produced in E. Coli as substrate.Phosphorylation of the substrate is detected and quantified using HTRFreagents supplied by Cisbio. These consist of an anti-GST antibodyconjugated to allophycocyanin (XL665) and an anti-phospho(Thr202/Tyr204) ERK antibody conjugated to europium-cryptate. These areused at a final concentration of 4 μg/ml and 0.8 μg/ml respectively. Theanti-phospho antibody recognises ERK1 dually phosphorylated on Thr202and Tyr204. When both antibodies are bound to ERK1 (i.e. when thesubstrate is phosphorylated), energy transfer from the cryptate to theallophycocyanin occurs following excitation at 340 nm, resulting influorescence being emitted that is proportional to the amount ofphosphorylated substrate produced. Fluorescence is detected using amultiwell fluorimeter.

Compounds are diluted in DMSO prior to addition to assay buffer and thefinal DMSO concentration in the assay is 1%.

The IC₅₀ is defined as the concentration at which a given compoundachieves 50% inhibition of control. IC₅₀ values are calculated using theXLfit software package (version 2.0.5).

Title compounds of Examples 5-20 and 22-24 exhibited an IC₅₀ of lessthan 0.5 μM in the assay described in Example 1. Some of these compoundsexhibited an IC₅₀ of less than 0.1 μM in the assay described inExample 1. Title compounds of Examples 21 and 25 exhibited an IC₅₀ ofless than 10 μM in the assay described in Example 1.

Example 2 bRaf Assay (MEK Activation Assay)

Constitutively activated bRaf mutant expressed in insect cells is usedas source of enzymatic activity.

The assay is carried out for 30 minutes in the presence of 200 μM ATPusing recombinant GST-MEK1 produced in E. Coli as substrate.Phosphorylation of the substrate is detected and quantified using HTRF,and reagents are supplied by Cisbio. These consist of an anti-GSTantibody conjugated to allophycocyanin (XL665) and an anti-phospho(Ser217/Ser221) MEK antibody conjugated to europium-cryptate. Theanti-phospho antibody recognises MEK dually phosphorylated on Ser217 andSer221 or singly phosphorylated on Ser217. When both antibodies arebound to MEK (i.e. when the substrate is phosphorylated), energytransfer from the cryptate to the allophycocyanin occurs followingexcitation at 340 nm, resulting in fluorescence being emitted that isproportional to the amount of phosphorylated substrate produced.Fluorescence is detected using a multi-well fluorimeter.

Compounds are diluted in DMSO prior to addition to assay buffer and thefinal DMSO concentration in the assay is 1%.

The IC₅₀ is defined as the concentration at which a given compoundachieves 50% inhibition of control. IC₅₀ values are calculated using theXLfit software package (version 2.0.5).

Example 3 Cell Proliferation Assay

Compounds are tested in a cell proliferation assay using the followingcell lines:

HCT 116 human colorectal carcinoma (ATCC)

A375 human malignant melanoma (ATCC)

Both cell lines are maintained in DMEM/F12 (1:1) media (Gibco)supplemented with 10% FCS at 37° C. in a 5% CO₂ humidified incubator.

Cells are seeded in 96-well plates at 2,000 cells/well and after 24hours they are exposed to different concentrations of compounds in 0.83%DMSO. Cells are grown for a further 72 h, and an equal volume ofCellTiter-Glo reagent (Promega) is added to each well. This lyses thecells and generates a luminescent signal proportional to the amount ofATP released (and therefore proportional to the number of cells in thewell) that can be detected using a multi-well luminometer.

The EC₅₀ is defined as the concentration at which a given compoundachieves 50% inhibition of control. IC₅₀ values are calculated using theXLfit software package (version 2.0.5).

In this assay, title compounds of Example 5-8, 11-13 and 18-20 exhibitedan EC₅₀ of less than 0.5 μM in both cell lines. Some of the titlecompounds of Examples 5-8, 11-13 and 18-20 exhibited an EC₅₀ of lessthan 0.1 μM in both cell lines. Title compounds of Examples 9-10 and14-17 exhibited an EC₅₀ of less than 0.8 μM in the HCT116 cell line.

Example 4 Phospho-ERK Cell-Based Assay

Compounds are tested in a cell-based phospho-ERK ELISA using thefollowing cell lines:

HCT116 human colorectal carcinoma (ATCC)

A375 human malignant melanoma (ATCC)

Both cell lines are maintained in DMEM/F12 (1:1) media (Gibco)supplemented with 10% FCS at 37° C. in a 5% CO₂ humidified incubator.

Cells are seeded in 96-well plates at 2,000 cells/well and after 24 hthey are exposed to different concentrations of compounds in 0.83% DMSO.Cells are grown for a further 2 h or 24 h, fixed with formaldehyde (2%final) and permeabilised with methanol. Following blocking with TBST-3%BSA, fixed cells are incubated with primary antibody (anti-phospho ERKfrom rabbit) over-night at 4° C. Cells are incubated with PropidiumIodide (DNA fluorescent dye) and detection of cellular p-ERK isperformed using an anti-rabbit secondary antibody conjugated to thefluorescent Alexa Fluor 488 dye (Molecular probes). The fluorescence isanalysed using the Acumen Explorer (TTP Labtech), a laser-scanningmicroplate cytometer, and the Alexa Fluor 488 signal is normalised tothe PI signal (proportional to cell number).

The EC₅₀ is defined as the concentration at which a given compoundachieves a signal half way between the baseline and the maximumresponse. EC₅₀ values are calculated using the XLfit software package(version 2.0.5).

In this assay, title compounds of Examples 5-8, 11-12 and 18-20exhibited an EC₅₀ of less than 0.02 μM in both cell lines. Some of thetitle compounds of Examples 5-8, 11-12 and 18-20 exhibited an EC₅₀ ofless than 0.01 μM in both cell lines. Title compounds of Examples 9-10and 13-17 exhibited an EC₅₀ of less than 0.05 μM in the HCT116 cellline.

Synthesis of Imidazo[1,5-a]Pyridines2-Fluoro-4-trimethylsilanyl-phenylamine

Method A, Step 1: (3-Fluoro-4-nitro-phenyl)-trimethylsilane

4-Chloro-2-fluoronitrobenzene (97.2 g, 0.55 mol) was dissolved inxylenes (208 ml) and hexamethyldisilane (306 g, 2.78 mol) was added.Argon was bubbled through the mixture for 20 min, then Pd(PPh₃)₄ (16.2g, 14 mmol) was added and the mixture was heated under continuous flowof argon at 150° C. for 1 hour. A balloon of argon was then fitted andthe mixture was heated at 150° C. for a further 60 hours. After coolingthe mixture was diluted with diethyl ether and filtered through a pad ofsilica. The filter cake was washed with further diethyl ether, and thecombined filtrates were concentrated in vacuo. Purification of theresultant residue by flash chromatography (SiO₂, 98:1:1pentane:CH₂Cl₂:Et₂O eluent) gave the title compound as an orange oil(76.7 g). Impure chromatography fractions were combined andconcentrated, and then subjected to vacuum distillation (b.p. 110° C., 6mbar) to give a further portion of the title compound as an orange oil(7.2 g, overall 83.9 g, 71%). ¹H NMR δ (DMSO-d₆): 0.30 (9 H, s), 7.56 (1H, d, J=8.02 Hz), 7.67 (1 H, dd, J=11.49, 1.14 Hz), 8.10 (1 H, t, J=7.66Hz).

Method A, Step 2: 2-Fluoro-4-trimethylsilanyl-phenylamine

A slurry of 10% wt. palladium on carbon (4.0 g) in IMS (25 mL) was addedto a solution of (3-fluoro-4-nitro-phenyl)-trimethylsilane (62.0 g, 0.29mol) in IMS (250 mL) and the reaction mixture flushed with nitrogen fivetimes then hydrogen three times. The reaction mixture was then stirredunder 3 bar pressure of hydrogen at room temperature for 4 hours. Thereaction mixture was then purged with nitrogen again before filteringthrough a pad of Celite® with ethyl acetate washings. The filtrate wasconcentrated under reduced pressure to give the title compound as alight brown oil (53.0 g, quantitative). ¹H NMR (CDCl₃) 7.16-7.09 (1H,m), 7.10 (1 H, d, J=7.75 Hz), 6.81 (1 H, t, J=8.16 Hz), 3.78 (2 H, s),0.26 (9 H, s).

Method B, Step 2: 2-Fluoro-4-trimethylsilanyl-phenylamine

To a solution of 4-bromo-2-fluoro-phenylamine (114 g, 0.6 mol) inanhydrous THF (750 mL) at −78° C. was added a 1.6M solution of nBuLi inhexanes (1500 mL, 2.4 mol) dropwise keeping the internal temperaturebelow −60° C., under an inert atmosphere. The reaction mixture wastreated dropwise with TMSCl (256 mL, 2.0 mol), keeping the internaltemperature below −60° C. The reaction mixture was allowed to warm to 0°C. over a 1 hour period and poured into ice-cold 2M HCl (ca. 1 L). Themixture was vigorously stirred for 10 min, then the organic layer wasseparated, and washed with water and a saturated solution of potassiumcarbonate, dried (Na₂SO₄), filtered and concentrated to give the titlecompound as a light brown oil (89 g, 81%).

4-Cyclopropyl-2-fluoro-phenylamine

Step 1: Trifluoro-methanesulfonic acid 3-fluoro-4-nitro-phenyl ester

To a solution of 3-fluoro-4-nitrophenol (12.5 g, 80 mmol) andtrifluoromethane sulfonic anhydride (26.8 mL, 160 mmol) in DCM (300 mL)at 0° C. was added triethylamine (44.6 mL, 320 mmol) dropwise. Thereaction mixture was stirred at 0° C. for 2 hours then allowed to warmto room temperature and stirred for 18 hours. The reaction was quenchedby the addition of water and the mixture extracted with DCM. The organiclayer was separated, washed with water and then dried (MgSO₄), filteredand concentrated in vacuo. The resultant residue was subjected to flashchromatography (Si-PPC, gradient 0 to 40% ethyl acetate in cylcohexane)to give the title compound as a yellow oil (12.8 g, 56% yield). ¹H NMR(DMSO-d₆, 400 MHz) 8.39 (1 H, t, J=8.83 Hz), 8.12 (1 H, dd, J=11.09,2.65 Hz), 7.67 (1 H, ddd, J=9.20, 2.62, 1.52 Hz).

Step 2: 4-Cyclopropyl-2-fluoro-1-nitro-benzene

A stirred suspension of trifluoro-methanesulfonic acid3-fluoro-4-nitro-phenyl ester (5.6 g, 19 mmol), cyclopropyl boronic acid(2.09 g, 23.3 mmol) Pd(dppf)Cl₂ (1.24 g, 1.5 mmol) and 2M aqueous cesiumcarbonate (30 mL, 60 mmol) in toluene (20 mL) was degassed before beingheated at 90° C. under an argon atmosphere for 2.5 hours. The reactionmixture was allowed to cool to room temperature before filtering througha pad of Celite®, washing with ethyl acetate. The filtrate was washed(water, brine), and then dried (MgSO₄), filtered and concentrated invacuo. The resultant residue was subjected to flash chromatography(Si-PPC, gradient 0-30% ethyl acetate in pentane) to give the titlecompound as a yellow solid (2.79 g, 81%). ¹H NMR (DMSO-d₆, 400 MHz) 8.03(1 H, t, J=8.39 Hz), 7.28 (1 H, dd, J=13.19, 1.91 Hz), 7.16 (1 H, dd,J=8.61, 1.90 Hz), 2.14-2.05 (1 H, m), 1.21-1.05 (2 H, m), 0.92-0.82 (2H, m).

Step 3: 4-Cyclopropyl-2-fluoro-phenylamine

A slurry of palladium on carbon (200 mg, 10% wt.) in IMS was added to adegassed solution of 4-cyclopropyl-2-fluoro-1-nitro-benzene (1.45 g, 8mmol) in IMS (50 mL), the atmosphere was evacuated and back-filled withnitrogen then re-evacuated and back-filled with hydrogen. The reactionmixture was stirred under 1 atmosphere pressure of hydrogen at roomtemperature for 24 hours before filtering through a pad of Celite® thenwashing with ethyl acetate. The filtrate was concentrated in vacuo togive the title compound as a pale purple residue (1.19 g, 98%). ¹H NMR(CDCl₃, 400 MHz) 6.72-6.63 (3 H, m), 3.56 (2 H, s), 1.83-1.75 (1 H, m),0.93-0.82 (2 H, m), 0.59-0.54 (2 H, m).

2-(2-Fluoro-4-trimethylsilanyl-phenylamino)-6-formylaminomethyl-nicotinicacid methyl ester

Step 1: 6-Chloro-2-(2-fluoro-4-trimethylsilanyl-phenylamino)nicotinicacid

To a cold (−78° C.) solution of 2-fluoro-4-trimethylsilanyl-phenylamine(64.7 g, 353 mmol) in anhydrous THF (170 mL) was added a solution ofLHMDS (555 mL, 1 M in hexanes, 555 mmol) dropwise over 45 minutes undera nitrogen atmosphere. After 2.5 hours at 78° C., a solution of2,6-dichloro-nicotinic acid (33.8 g, 177 mmol) in anhydrous THF (100 mL)was added. The reaction mixture was stirred at −78° C. for 30 minutesthen allowed to warm to room temperature. After 18 hours stirring atroom temperature the reaction was quenched with crushed ice and the pHadjusted to pH 1 by the addition of concentrated HCl (ca. 90 mL). Theresultant solution was extracted with ethyl acetate and the organiclayer washed with water followed by brine, dried (Na₂SO₄), filtered andevaporated in vacuo. The resultant residue was triturated three timessuccessively with methanol and filtered to afford the title compound asa yellow solid (46.7 g, 78%). LCMS (method B): R_(T)=4.83 min, M+H⁺=339.

Step 2: 6-Chloro-2-(2-fluoro-4-trimethylsilanyl-phenylamino)-nicotinicacid methyl ester

To a suspension of6-chloro-2-(2-fluoro-4-trimethylsilanyl-phenylamino)-nicotinic acid(33.7 g, 99.5 mmol) in dichloromethane (500 mL) at 0° C. was added DIPEA(17.1 mL, 99.5 mmol). The reaction mixture was stirred for 10 minutes,then DMF (2 mL) and oxalyl chloride (8.7 mL, 99.5 mmol) were addeddropwise (CAUTION: EFFERVESCENCE). The reaction mixture was stirred atroom temperature for 2 hours and then added dropwise to a solution ofDIPEA (17.1 mL, 99.5 mmol) in MeOH (500 mL) at 0° C. over a 45 minutesperiod. The reaction mixture was stirred at room temperature for 18hours before being concentrated in vacuo. The resultant residue wasdissolved in ethyl acetate and washed with a saturated aqueous solutionof sodium hydrogen carbonate, followed by water, then brine, dried(Na₂SO₄), filtered and evaporated in vacuo to afford the title compoundas a brown foam which was used without purification into the next step(36.4 g). LCMS (method B) R_(T)=5.35 min, M+H⁺=353.

Step 3: 6-Cyano-2-(2-fluoro-4-trimethylsilanyl-phenylamino)-nicotinicacid methyl ester

A degassed suspension of6-chloro-2-(2-fluoro-4-trimethylsilanyl-phenylamino)-nicotinic acidmethyl ester (4.8 g, 12.4 mmol), zinc cyanide (1.2 g, 10.2 mmol), andPd(PPh₃)₄ (1.6 g, 1.36 mmol) in dimethylformamide (14 mL) was subjectedto microwave irradiation at 190° C. for 20 minutes. This procedure wasrepeated seven times and all the reaction mixtures were combined andconcentrated in vacuo. The resultant residue was dissolved in ethylacetate and washed with a saturated aqueous solution of sodium hydrogencarbonate. The aqueous layer was separated and extracted with ethylacetate three times. The combined organic extracts were washed withwater and then brine, dried (Na₂SO₄), filtered and evaporated in vacuo.The resultant residue was subjected to flash chromatography (silica,gradient 0% to 100%, diethyl ether in pentane) to afford the titlecompound as a yellow solid (18.2 g). LCMS (method B): R_(T)=4.74 min,M+H⁺=344.

Step 4:6-Aminomethyl-2-(2-fluoro-4-trimethylsilanyl-phenylamino)nicotinic acidmethyl ester

To a suspension of6-cyano-2-(2-fluoro-4-trimethylsilanyl-phenylamino)-nicotinic acidmethyl ester (13.1 g, 38.2 mmol) in methanol (285 mL) was added cobalt(II) chloride (18.2 g, 76.4 mmol). The reaction mixture was cooled to 0°C. and sodium borohydride (14.5 g, 382 mmol) was added in small portionsover 20 minutes (CAUTION: EFFERVESCENCE). The reaction mixture wasstirred at 0° C. for 1 hour. The reaction was quenched by the additionof concentrated hydrochloric acid (50 mL) and the mixture stirred at 0°C. for 10 minutes and at room temperature for 45 minutes.Diethylenetriamine (9 mL) was then added and the mixture stirred for afurther 15 minutes. The reaction mixture was filtered to remove a whitesolid, which was washed with dichloromethane. The filtrate wasconcentrated in vacuo and the resultant residue was dissolved in ethylacetate and washed with a saturated solution of sodium hydrogencarbonate, followed by water then brine. The organic phase was isolated,dried (Na₂SO₄), filtered and concentrated in vacuo to afford the titlecompound as a brown solid (13.2 g, 100%). LCMS (method B): R_(T)=2.82min, M+H⁺=348.

Step 5:2-(2-Fluoro-4-trimethylsilanyl-phenylamino)-6-formylaminomethyl-nicotinicacid methyl ester

A solution of6-aminomethyl-2-(2-fluoro-4-trimethylsilanyl-phenylamino)-nicotinic acidmethyl ester (13.2 g, 38.2 mmol) in formic acid (200 mL) and aceticanhydride (40 mL) was stirred at ambient temperature for 1 hour. Thereaction mixture was concentrated in vacuo and the residue azeotropedwith toluene. The resultant residue was dissolved in dichloromethane andwashed with a saturated aqueous solution of sodium hydrogen carbonate,followed by brine. The organic phase was isolated, dried (Na₂SO₄),filtered and concentrated in vacuo to afford the title compound as ayellow solid (12.7 g, 89%). LCMS (method B): R_(T)=4.17 min, M+H⁺=376.

5-Chloro-imidazo[1,5-a]pyridine-6-carboxylic acid methyl ester

Step 1, Method A: 6-Bromomethyl-2-chloronicotinic acid methyl ester

To a solution of 2-chloro-6-methylnicotinic acid methyl ester (100 g,0.54 mol) in DCE (1.0 L) was added re-crystallised N-bromosuccinimide(124.7 g, 0.70 mol) and benzoylperoxide (13.1 g, 0.05 mol). The reactionmixture was heated at 70° C. for 16 hours, during which the reagentsdissolved to give a dark red solution. The reaction mixture was dilutedwith saturated aqueous sodium hydrogen carbonate solution (200 mL)causing the red colour to fade to yellow. The aqueous layer wasextracted with DCM (2×100 mL). The combined organic fractions werewashed with brine (100 mL), dried (MgSO₄) and concentrated in vacuo togive the crude product (<138 g, <0.54 mol) as a yellow oil containingapproximately 40% desired product. ¹H NMR (CDCl₃, 400 MHz) 8.18 (1H, d,J=8.0 Hz), 7.48 (1H, d, J=7.9 Hz), 4.51 (2H, s), 3.94 (3H, s).

Step 1, Method B: Alternative method 6-Bromomethyl-2-chloronicotinicacid methyl ester

To a mechanically stirred solution of 2-chloro-6-methylnicotinic acidmethyl ester (147 g, 0.79 mol) in DCE (1.5 L) was added1,3-dibromo-5,5-dimethylhydantoin (181.8 g, 0.635 mol) and MEN (6.35 g,0.04 mol). The reaction mixture was heated at 65° C. for 72 hours,during which the reagents dissolved to give a dark red/brown solution.The reaction mixture was cooled and diluted with saturated aqueoussodium hydrogen carbonate solution (1 L) causing the red colour to fadeto yellow. The layers were separated, and the aqueous layer wasextracted with DCM (2×750 mL). The combined organic fractions werewashed with water (1 L), sat. saline (1 L), dried (MgSO₄) andconcentrated in vacuo. The resultant yellow oil (235 g), containingapproximately 46% desired product, was used crude in the next stepwithout further purification. ¹H NMR (CDCl₃, 400 MHz) 8.18 (1H, d, J=8.0Hz), 7.48 (1H, d, J=7.9 Hz), 4.51 (2H, s), 3.94 (3H, s).

Step 2, Method A: 2-Chloro-6-diformylaminomethylnicotinic acid methylester

To a solution of crude 6-bromomethyl-2-chloronicotinic acid methyl ester(<138 g, <0.54 mol) in DMF (400 mL) was added sodium diformamide (56.3g, 0.59 mol) and the reaction mixture stirred at room temperature for 16hours. The reaction mixture rapidly darkened and a small exotherm wasobserved. The reaction mixture was concentrated in vacuo and the residuedissolved in ethyl acetate (200 mL). The resultant solution was washedwith water (400 mL) and the aqueous layer extracted with ethyl acetate(2×200 mL). The combined organic extracts were washed with brine (100mL), dried (MgSO₄) and concentrated in vacuo. The resultant residue wasdry-loaded onto silica (150 g) and the residue subjected to flashchromatography (SiO₂ 400 g, 40% ethyl acetate in cyclohexane) to yieldthe title compound as a yellow solid (46 g, 33% over two steps). ¹H NMR(CDCl₃, 400 MHz) 8.46 (2H, br s), 7.56 (1H, d, J=7.7 Hz), 6.66 (1H, d,J=7.9 Hz), 4.39 (2H, br s), 3.36 (3H, s).

Step 2, Method B: 2-Chloro-6-diformylaminomethylnicotinic acid methylester

To a solution of crude 6-bromomethyl-2-chloronicotinic acid methyl ester(235 g) in DMF (500 mL) was added sodium diformamide (82 g, 0.878 mol)portion wise, maintaining the temperature below 30° C., and the reactionmixture stirred at room temperature for 16 hours (N.B. the reactionmixture rapidly darkened and a small exotherm was observed). Thereaction mixture was concentrated in vacuo and the residue dissolved inethyl acetate (400 mL). The resultant solution was washed with water(2×400 mL) and the aqueous layer extracted with ethyl acetate (2×300mL). The combined organic extracts were washed with brine (200 mL),dried (MgSO₄) and concentrated in vacuo. The resultant residue wasdry-loaded onto silica (200 g) and the residue subjected to flashchromatography (SiO₂ 300 g, 10-30% ethyl acetate in cyclohexane) toyield the title compound as a yellow solid (90.2 g, 44% over two steps).¹H NMR (CDCl₃, 400 MHz) 8.46 (2H, br s), 7.56 (1H, d, J=7.7 Hz), 6.66(1H, d, J=7.9 Hz), 4.39 (2H, br s), 3.36 (3H, s).

Step 3, Method A: 2-Chloro-6-formylaminomethylnicotinic acid methylester

To a solution of 2-chloro-6-diformylaminomethylnicotinic acid methylester (53.0 g, 0.21 mol) in methanol (300 mL) was added water (3.72 mL,0.21 mol) and formic acid (15.6 mL, 0.42 mol) before the reactionmixture was heated at reflux for 16 hours. The reaction mixture wasconcentrated in vacuo and the residue dissolved in ethyl acetate (200mL). The resultant solution was washed with water (200 mL) and theaqueous layer extracted with ethyl acetate (2×100 mL). The combinedorganic extracts were washed with brine (100 mL), dried (MgSO₄) andconcentrated in vacuo to yield the title compound as an orange oil whichsolidified on standing (42.6 g, 90%). ¹H NMR (CDCl₃, 400 MHz) 8.34 (1H,s), 8.17 (1H, d, J=8.0 Hz), 7.31 (1H, d, J=7.8 Hz), 6.63 (1H, br s),4.63 (2H, d, J=5.6 Hz), 3.96 (3H, s).

Step 3, Method B: 2-Chloro-6-formylaminomethylnicotinic acid methylester

To a solution of 2-chloro-6-diformylaminomethylnicotinic acid methylester (90.2 g, 0.352 mol) in methanol (530 mL) was added water (8 mL,0.44 mol) and formic acid (27.6 mL, 0.73 mol) before the reactionmixture was heated at gentle reflux for 16 hours. The reaction mixturewas concentrated in vacuo and the residue dissolved in ethyl acetate(400 mL). The resultant solution was washed with water (400 mL) and theaqueous layer extracted with ethyl acetate (2×200 mL). The combinedorganic extracts were washed with brine (300 mL), dried (MgSO₄) andconcentrated in vacuo to yield the title compound as an orange oil whichsolidified on standing (79.78 g, 99%). ¹H NMR (CDCl₃, 400 MHz) 8.34 (1H,s), 8.17 (1H, d, J=8.0 Hz), 7.31 (1H, d, J=7.8 Hz), 6.63 (1H, br s),4.63 (2H, d, J=5.6 Hz), 3.96 (3H, s).

Step 4: 5-Chloroimidazo[1,5-a]pyridine-6-carboxylic acid methyl ester

To a suspension of 2-chloro-6-formylaminomethylnicotinic acid methylester (42.6 g, 0.19 mol) in toluene (400 mL) was added phosphorous (V)oxychloride (18.2 mL, 0.20 mol) and the reaction mixture heated at 65°C. for 1.5 hours. The reaction mixture was cooled to room temperatureand diluted with ethyl acetate (200 mL) before treating with sodiumhydroxide solution (2 M) to adjust pH˜8. The layers were separated andthe aqueous layer extracted with ethyl acetate (2×100 mL). The combinedorganic extracts were washed with brine (100 mL), dried (MgSO₄) thencharcoal (˜5 g) was added and the solution mixed for 5 minutes beforebeing filtered and concentrated in vacuo to yield the title compound asa tan solid (34.4 g, 88%) ¹H NMR (CDCl₃, 400 MHz) 8.52 (1H, s), 7.57(1H, s), 7.45 (1H, d, J=9.3 Hz), 7.25 (1H, d, J=9.1 Hz), 3.97 (3H, s).

5-(2-Fluoro-4-iodophenylamino)-imidazo[1,5-a]pyridine-6-carboxylic acid

Step 1: 2-(2-Fluoro-4-iodophenylamino)-6-formylaminomethylnicotinic acidmethyl ester

To a solution of2-(2-fluoro-4-trimethylsilanylphenylamino)-6-formylaminomethyl-nicotinic acid methyl ester (10.3 g, 27.4 mmol) in DCM (275 mL)at 0° C. was added dropwise iodine monochloride as a solution in DCM(54.9 mL, 1M, 54.9 mmol). The reaction mixture was stirred at 0° C. for1 hour. The reaction mixture was washed with aqueous sodiummetabisulfite (100 mL, 0.5 M) and the aqueous layer extracted twice withethyl acetate (2×50 mL). The combined organic extracts were washed withbrine (50 mL), dried (MgSO₄), filtered and concentrated in vacuo to givethe title compound as an orange gum (11.6 g, 100%). LCMS (Method B):R_(T)=3.72 min, M+H⁺=430.

Step 2:5-(2-Fluoro-4-iodophenylamino)-imidazo[1,5-a]pyridine-6-carboxylic acidmethyl ester

To a suspension of2-(2-fluoro-4-iodophenylamino)-6-formylaminomethylnicotinic acid methylester (11.6 g, 27.4 mmol) in toluene (160 mL) was added phosphorous (V)oxychloride (5.1 mL, 54.8 mmol) and the reaction mixture heated at 95°C. for 1 hour. The reaction mixture was concentrated in vacuo and theresultant residue poured onto ice. The mixture was washed with aqueoussaturated sodium hydrogen carbonate solution (40 mL) and the aqueouslayer extracted twice with ethyl acetate (2×30 mL). The combined organicextracts were washed with brine (30 mL), dried (MgSO₄), filtered andconcentrated in vacuo. The resultant residue was subjected to flashchromatography (SiO₂, gradient 0-70% ethyl acetate in DCM) to yield thetitle compound as a brown oil (5.6 g, 50%). LCMS (Method B): R_(T)=3.62min, M+H⁺=412.

Step 3:5-(2-Fluoro-4-iodophenylamino)-imidazo[1,5-a]pyridine-6-carboxylic acid

To a solution of5-(2-fluoro-4-iodophenylamino)-imidazo[1,5-a]pyridine-6-carboxylic acidmethyl ester (5.6 g, 13.6 mmol) in IMS (50 mL) was added aqueous sodiumhydroxide (27.2 mL, 1M, 27.2 mmol) and the reaction mixture stirred at65° C. for 2 hours. The reaction mixture was concentrated in vacuo toremove the IMS. The resultant solution was acidified to pH ˜5 byaddition of aqueous hydrochloric acid (1M) causing a precipitate toform. The product was collected by filtration and dried under vacuum at45° C. to yield the title compound as a beige solid (5.4 g, 100%). LCMS(Method B): R_(T)=2.79 min, M+H⁺=398.

5-(2-Fluoro-4-iodophenylamino)-imidazo[1,5-a]pyridine-6-carboxylic acidmethyl ester, Method A

To a solution of lithium bis(trimethylsilyl)amide (9.98 mL, 1M solution,9.98 mmol) in THF (20 mL) under nitrogen at −70° C. was added dropwise,over 15 minutes, a solution of 2-fluoro-4-iodo aniline (1.01 g, 4.28mmol) and 5-chloro-imidazo[1,5-a]pyridine-6-carboxylic acid methyl ester(1.0 g, 4.75 mmol) in THF (20 mL) giving a bright red solution. Afterstirring for 30 minutes at −78° C. the reaction mixture was allowed towarm and then quenched with saturated aqueous ammonium chloride (200mL). The mixture was extracted twice with ethyl acetate, before thecombined organic extracts were dried (MgSO₄), filtered and concentratedin vacuo. The resultant residue was subjected to flash chromatography(Si-PPC, gradient 0-40% ethyl acetate in cyclohexane) to yield the titlecompound as a yellow solid (1.15 g, 65%). LCMS (Method B): R_(T)=3.54min, M+H⁺=412.

5-(2-Fluoro-4-iodophenylamino)-imidazo[1,5-a]pyridine-6-carboxylic acidmethyl ester, Method B

To a stirred suspension 2-fluoro-4-iodo aniline (53.95 g, 0.256 mol) and5-chloro-imidazo[1,5-a]pyridine-6-carboxylic acid methyl ester (62.0 g,0.253 mol) in THF (500 mL) under nitrogen at −78° C., a solution oflithium bis(trimethylsilyl)amide (544 mL, 1M solution, 0.544 mol) wasadded dropwise over 1 hr, maintaining the temperature below −65° C.,giving a red/brown solution. After stirring for 30 minutes at −78° C.the reaction mixture was allowed to warm to −30° C. and then quenchedwith addition water (100 mL). The solvent was removed in vacuo, beforediluting with water (500 ml) and the mixture was extracted with2-methyltetrahydrofuran (2×500 mL). The combined organic extracts werewashed with water, then brine, dried (MgSO₄), filtered and concentratedin vacuo. The resultant residue was triturated tert-butyl methyl ether(600 mL) to yield product as yellow/brown solid (87.2 g 83%). LCMS(Method B): R_(T)=3.54 min, [M+H]⁺=412.

5-(4-Bromo-2-fluorophenylamino)-imidazo[1,5-a]pyridine-6-carboxylic acid

Step 1: 2-(4-Bromo-2-fluorophenylamino)-6-formylaminomethylnicotinicacid methyl ester

To a solution of2-(2-fluoro-4-trimethylsilanylphenylamino)-6-formylaminomethyl-nicotinic acid methyl ester (11.6 g, 30.9 mmol) in DCM (300 mL)at −30° C. was added N-bromo succinimide (5.56 g, 30.9 mmol)portionwise. The reaction mixture was stirred at −30° C. for 30 minutes.The reaction mixture was concentrated in vacuo and the residuepartitioned between saturated aqueous sodium hydrogen carbonate andethyl acetate. The organic layer was separated and washed with water,dried (Na₂SO₄), filtered and concentrated in vacuo to give the titlecompound as an orange gum (11.8 g, 100%). LCMS (Method B): R_(T)=3.67min, M+H⁺=382/384.

Step 2:5-(4-Bromo-2-fluorophenylamino)-imidazo[1,5-a]pyridine-6-carboxylic acidmethyl ester

To a solution of2-(4-Bromo-2-fluorophenylamino)-6-formylaminomethylnicotinic acid methylester (11.8 g, 30.9 mmol) in toluene (550 mL) was added phosphorous (V)oxychloride (3.16 mL, 34 mmol) and the reaction mixture heated at 95° C.for 1 hour. The reaction mixture was concentrated in vacuo and treatedwith aqueous saturated sodium hydrogen carbonate solution then extractedtwice with ethyl acetate. The combined organic fractions were washedwith brine, dried (Na₂SO₄) and concentrated in vacuo. The resultantresidue was subjected to flash chromatography (Si-PPC, gradient 0-30%ethyl acetate in DCM) to yield the title compound as a brown oil (5.4 g,49%). LCMS (Method B): R_(T)=3.56 min, M+H⁺=364/366.

Step 3: 5-(4-Bromo-2-fluorophenylamino)-imidazo carboxylic acid

To a solution of5-(4-Bromo-2-fluorophenylamino)-imidazo[1,5-a]pyridine-6-carboxylic acidmethyl ester (5.4 g, 15 mmol) in IMS (110 mL) was added aqueous sodiumhydroxide (30 mL, 1M, 30 mmol) and the reaction mixture stirred at 65°C. for 1.5 hours. The reaction mixture was concentrated in vacuo to 50mL volume and the resultant solution was acidified to pH ˜2 by additionof aqueous hydrochloric acid (1M) causing a precipitate to form. Theprecipitate was collected by filtration and dried under vacuum at 35° C.to yield the title compound as a dark tan solid (4.48 g, 85%). LCMS(Method B): R_(T)=2.81 min, M+H⁺=350/352.

5-(2-Fluoro-4-cyclopropylphenylamino)-imidazo[1,5-a]pyridine-6-carboxylicacid

Step 1:5-(2-Fluoro-4-cyclopropylphenylamino)-imidazo[1,5-a]pyridine-6-carboxylicacid methyl ester

To a solution of 2-fluoro-4-cyclopropyl aniline (395 mg, 2.61 mmol) and5-chloro-imidazo[1,5-a]pyridine-6-carboxylic acid methyl ester (500 mg,2.37 mmol) in THF under nitrogen at −70° C. (20 mL) was added lithiumbis(trimethylsilyl)amide (4.98 mL, 1M solution, 4.98 mmol) dropwise.After stirring for 1 hour at −70° C. the reaction mixture was allowed towarm and then quenched with saturated aqueous ammonium chloride. Themixture was extracted with ethyl acetate (150 mL), the organic extractdried (Na₂SO₄), filtered and concentrated in vacuo. The resultantresidue was subjected to flash chromatography (Si-PPC, gradient 0-50%ethyl acetate in cyclohexane) to yield the title compound (573 mg, 60%).LCMS (Method B): R_(T)=3.60 min, MA-H⁺=326.

Step 2:5-(2-Fluoro-4-cyclopropylphenylamino)-imidazo[1,5-a]pyridine-6-carboxylicacid

To a solution of5-(2-fluoro-4-cyclopropylphenylamino)-imidazo[1,5-a]pyridine-6-carboxylicacid methyl ester (573 mg, 1.73 mmol) in methanol (20 mL) was addedaqueous sodium hydroxide (10 mL, 1M, 10 mmol) and the reaction mixturestirred at 70° C. for 30 minutes. The reaction mixture was concentratedin vacuo to −20 mL volume and the resultant solution diluted with water(20 mL) and filtered. The filtrate was acidified to pH 1 by addition ofaqueous hydrochloric acid (1M) causing a precipitate to form. Theprecipitate was collected by filtration and dried under vacuum at 45° C.to yield the title compound as a dark tan solid (476 mg, 87%). LCMS(Method B): R_(T)=2.81 min, M+H⁺=318.

5-(2-Fluoro-4-methansulfanyl-phenylamino)-imidazo[1,5-a]pyridine-6-carboxylicacid, Method A

Step 1:5-(2-Fluoro-4-methylsulfanyl-phenylamino)-imidazo[1,5-a]pyridine-6-carboxylicacid methyl ester

To a solution of 2-fluoro-4-methanesulfanyl phenyl amine (410 mg, 2.61mmol) and 5-chloro-imidazo[1,5-a]pyridine-6-carboxylic acid methyl ester(500 mg, 2.37 mmol) in THF under nitrogen at −70° C. (20 mL) was addedlithium bis(trimethylsilyl)amide (4.98 mL, 1M solution, 4.98 mmol)dropwise. After stirring for 30 minutes at −70° C. the reaction mixturewas allowed to warm and then quenched with saturated aqueous ammoniumchloride. The mixture was extracted with ethyl acetate (150 mL), theorganic extract washed with brine, dried (Na₂SO₄), filtered andconcentrated in vacuo. The resultant residue was subjected to flashchromatography (Si-PPC, gradient 0-50% ethyl acetate in cyclohexane) toyield the title compound (471 mg, 73%). LCMS (Method B): R_(T)=3.39 min,M+H⁺=332.

Step 2:5-(2-Fluoro-4-methansulfanyl-phenylamino)-imidazo[1,5-a]pyridine-6-carboxylicacid

To a solution of5-(2-fluoro-4-methanesulfanyl-phenylamino)-imidazo[1,5-a]pyridine-6-carboxylicacid methyl ester (471 mg, 1.45 mmol) in methanol (20 mL) was addedaqueous sodium hydroxide (10 mL, 1M, 10 mmol) and the reaction mixturestirred at 70° C. for 30 minutes. The reaction mixture was concentratedin vacuo to −20 mL volume and the resultant solution diluted with water(20 mL) before being acidified to pH ˜1 by addition of aqueoushydrochloric acid (1M) causing a precipitate to form. The precipitatewas collected by filtration and dried under vacuum at 45° C. to yieldthe title compound as a dark tan solid (413 mg, 87%). LCMS (Method B):R_(T)=2.98 min, [M+H]⁺=312.

5-(2-Fluoro-4-methylsulfanyl-phenylamino)-imidazo[1,5-a]pyridine-6-carboxylicacid, Method B

Step 1: Pyridine-2,5-dicarboxylic acid dimethyl ester

To a suspension of pyridine-2,5-dicarboxylic acid (20 g, 120 mmol) indichloromethane (396 mL) and DMF (6.6 mL) was added oxalyl chloride(60.96 g, 480 mmol) dropwise over 20 minutes. After 16 hours at ambienttemperature, the reaction mixture was concentrated in vacuo and theresidue azeotroped with toluene. The residue was taken up in cold (0°C.) methanol (276 mL) and stirred for 15 minutes. The resultant solutionwas concentrated in vacuo and the residue taken up in ethyl acetate. Themixture was washed with a saturated aqueous solution of sodiumbicarbonate, water and brine. A portion of the product was collected asa white precipitate. The organic phase was isolated, dried (Na₂SO₄),filtered and concentrated in vacuo to afford the title compound as awhite solid (combined material obtained: 22.93 g, 98%). LCMS (method B):R_(T)=2.48 min, [M+H]⁺=196.

Step 2: 1-Oxy-pyridine-2,5-dicarboxylic acid dimethyl ester

To a cold (0° C.) solution of pyridine-2,5-dicarboxylic acid dimethylester (22.93 g, 118 mmol) in dichloromethane (472 mL) was added3-chloroperbenzoic acid (62.5 g, 278 mmol) portionwise. The reactionmixture was allowed to warm to ambient temperature. After stirring for18 hours, the reaction mixture was concentrated in vacuo, and theresultant residue was adsorbed onto HMN and subjected to flashchromatography (Si-PPC, gradient 0% to 100%, ethyl acetate in hexane) toafford the title compound as a pale yellow oil (17.08 g, 69%). LCMS(method B): R_(T)=1.64 min, [M+H]⁺=212.

Step 3: 6-Chloro-pyridine-2,5-dicarboxylic acid dimethyl ester

To a solution of 1-oxy-pyridine-2,5-dicarboxylic acid dimethyl ester(17.08 g, 81 mmol) in toluene (450 mL) was added phosphorous oxychloride(8.3 mL, 89 mmol). The reaction mixture was heated to 95° C. and stirredfor 1.5 hours. The reaction was quenched by the addition of water andthe mixture diluted with ethyl acetate. The solution was washed with asaturated aqueous solution of sodium bicarbonate, water and brine. Theorganic phase was isolated, dried (Na₂SO₄), filtered and concentrated invacuo to afford the title compound as a pale yellow solid (11.97 g, 65%)which was used without purification in the next step. LCMS (method B):R_(T)=2.77 min, [M+H]⁺=230.

Step 4: 2-Chloro-6-hydroxymethyl-nicotinic acid methyl ester

A cold (0° C.) suspension of calcium chloride (19.54 g, 176 mmol) andsodium borohydride (4.18 g, 110 mmol) in anhydrous ethanol (176 mL) andanhydrous THF (88 mL) was stirred for 1 hour, after which6-chloro-pyridine-2,5-dicarboxylic acid dimethyl ester (9.97 g, 44 mmol)was added. After stirring at 0° C. for a further 6 hours, the reactionwas quenched by the addition of H₂SO₄ (35 mL, 5M). The reaction mixturewas diluted with ethyl acetate and filtered through Celite®. Thefiltrate was washed with 1M NaOH, water and brine, the organic phase wasisolated, dried (Na₂SO₄), filtered and concentrated in vacuo. Theresultant residue was subjected to flash chromatography (Si-PPC,gradient 0% to 100%, ethyl acetate in hexane) to afford the titlecompound as a yellow oil (6.14 g, 69%). LCMS (method B): R_(T)=2.34 min,[M+H]⁺=202.

Step 5: 6-Azidomethyl-2-chloro-nicotinic acid methyl ester

To a cold (0° C.) solution of 2-chloro-6-hydroxymethyl-nicotinic acidmethyl ester (4.98 g, 24.8 mmol) in dichloromethane (161 mL) was addedmesyl chloride (2.5 mL, 29.8 mmol). The reaction mixture was allowed towarm to room temperature and stirred for 30 minutes. The mixture wasdiluted with ethyl acetate and washed with a saturated aqueous solutionof sodium bicarbonate, water and brine. The organic phase was isolated,dried (Na₂SO₄), filtered and concentrated in vacuo. The resultantresidue was taken up in dimethylformamide (62 mL) and sodium azide (4.03g, 62 mmol) added. After stirring at room temperature for 16 hours, thereaction mixture was cooled to 0° C., quenched with water (ca. 50 mL),and extracted three times with ethyl acetate. The combined organicextracts were washed with water and brine, dried (Na₂SO₄), filtered andconcentrated in vacuo. The residue was subjected to flash chromatography(Si-PPC, gradient 0% to 50%, ethyl acetate in hexane) to afford thetitle compound as a pale yellow oil (4.76 g, 85%). LCMS (method B):R_(T)=3.22 min, [M+H]⁺=227.

Step 6: 6-Aminomethyl-2-chloro-nicotinic acid methyl ester

To a solution of 6-azidomethyl-2-chloro-nicotinic acid methyl ester(4.75 g, 21 mmol) in THF (189 mL) and water (3.6 mL) was addedtriphenylphosphine (11 g, 42 mmol), the reaction mixture was heated at45° C. for 16 hours. The reaction mixture was concentrated under reducedpressure and the residue azeotroped with methanol. The resultant residuewas subjected to flash chromatography (Si-PPC, gradient 0% to 10%,methanol in dichloromethane) to afford the title compound as a yellowsolid. LCMS (method B): R_(T)=2.65 min, [M+H]⁺=201.

Step 7: 2-Chloro-6-formylaminomethyl-nicotinic acid methyl ester

To a solution of 6-aminomethyl-2-chloro-nicotinic acid methyl ester (740mg, 3.7 mmol) in formic acid (18.5 mL) was added acetic anhydride (3.7mL). The reaction mixture was stirred at room temperature for 1.5 hours.The reaction mixture was concentrated in vacuo and azeotroped threetimes with toluene to afford the title compound as a yellow oil (757 mg,90%) which was used without purification in the next step. LCMS (methodB): R_(T)=2.20 min, [M+H]⁺=229.

Step 8:2-(2-Fluoro-4-methylsulfanyl-phenylamino)-6-formylaminomethyl-nicotinicacid methyl ester

To a solution of 2-chloro-6-formylaminomethyl-nicotinic acid methylester (123 mg, 0.54 mmol) in toluene (1.6 mL) was added potassiumphosphate (119 mg, 0.76 mmol), 2-fluoro-4-methylsulfanyl-phenylamine(102 mg, 0.65 mmol), tris(dibenzylideneacetone)dipalladium (12.8 mg,0.014 mmol) anddicyclohexyl-(2′,6′-diisopropoxy-biphenyl-2-yl)-phosphane (25 mg, 0.054mmol). The reaction mixture was degassed with argon then heated at 100°C. After 25 hours, the reaction mixture was cooled, diluted with ethylacetate and washed with a saturated aqueous solution of ammoniumchloride, water then brine. The organic phase was isolated, dried(Na₂SO₄), filtered and concentrated in vacuo. The residue was trituratedwith ethyl acetate to afford the title compound as a bright yellow solid(43 mg, 23%). LCMS (method B): R_(T)=3.53 min, [M+H]⁺=350.

Step 9:5-(2-Fluoro-4-methylsulfanyl-phenylamino)-imidazo[1,5-a]pyridine-6-carboxylicacid methyl ester

To a suspension of2-(2-fluoro-4-methylsulfanyl-phenylamino)-6-formylaminomethyl-nicotinicacid methyl ester (309 mg, 0.89 mmol) in toluene (15.6 mL) was addedphosphorous oxychloride (91 μl, 0.98 mmol) and the reaction mixtureheated to 95° C. and stirred for 1 hour. The cooled reaction mixture wasquenched by the addition of water (ca. 2 mL) then concentrated in vacuo.The resultant residue was taken up in ethyl acetate and washed withwater followed by a saturated aqueous solution of sodium bicarbonate andbrine. The organic phase was isolated, dried (Na₂SO₄), filtered,concentrated in vacuo, and the residue subjected to flash chromatography(Si-PPC, gradient 0% to 40%, ethyl acetate in hexane) to afford thetitle compound as a yellow solid (150 mg, 51%). LCMS (method B):R_(T)=3.44 min, [M+H]⁺=332.

Step 10:5-(2-Fluoro-4-methylsulfanyl-phenylamino)-imidazo[1,5-a]pyridine-6-carboxylicacid

To a solution of5-(2-fluoro-4-methylsulfanyl-phenylamino)-imidazo[1,5-a]pyridine-6-carboxylicacid methyl ester (150 mg, 0.45 mmol) in IMS (10 mL) was added sodiumhydroxide (0.5 mL, 1M aqueous solution, 0.5 mmol), the reaction mixtureheated at 65° C. for 1.5 hours. The reaction mixture was concentrated invacuo then taken up in water (ca. 15 mL), the aqueous solution waswashed with diethyl ether before the pH was adjusted to pH 3 using 1MHCl, resulting in precipitation of a brown solid. The precipitate wasextracted using ethyl acetate, the organic phase was isolated and washedwith water followed by brine, dried (Na₂SO₄), filtered and concentratedunder reduced pressure to afford the title compound as a brown solid(109 mg, 76%). ¹H NMR (CD₃OD): 7.67 (1 H, s), 7.44 (1 H, d, J=9.53 Hz),7.39 (1 H, d, J=0.83 Hz), 7.24 (1 H, dd, J=9.57, 0.80 Hz), 7.15 (1 H,dd, J=11.47, 2.12 Hz), 7.02-7.01 (1 H, m), 6.76 (1 H, t, J=8.49 Hz),2.49 (3 H, s).

5-Fluoro-2-(2-fluoro-4-trimethylsilanyl-phenylamino)-6-formylaminomethyl-nicotinicacid methyl ester

Step 1:6-Chloro-5-fluoro-2-(2-fluoro-4-trimethylsilanyl-phenylamino)-nicotinicacid

To a cold (−78° C.) solution of 2-fluoro-4-trimethylsilanyl-phenylamine(19.2 g, 105 mmol) in anhydrous THF (50 mL) was added a solution ofLHMDS (160 mL, 1 M in hexanes, 160 mmol) dropwise over 45 minutes undera nitrogen atmosphere. After 2 hours at −78° C., a solution of2,6-dichloro-5-fluoro-nicotinic acid (10.5 g, 50 mmol) in anhydrous THF(30 mL) was added. The mixture was stirred at −78° C. for 1 hour thenallowed to warm to ambient temperature. After 18 hours stirring atambient temperature the reaction was quenched with water and adjusted topH 2 by the addition of concentrated HCl. The solution was extractedwith ethyl acetate and the organic layer was isolated, washed with waterfollowed by brine, dried (Na₂SO₄), filtered and evaporated in vacuo. Theresultant residue was triturated with methanol and filtered to affordthe title compound as a yellow solid (8.7 g, 49%). LCMS (method B):R_(T)=4.92 min, [M+H]⁺=357.

Step 2:6-Chloro-5-fluoro-2-(2-fluoro-4-trimethylsilanyl-phenylamino)-nicotinicacid methyl ester

To a suspension of6-chloro-5-fluoro-2-(2-fluoro-4-trimethylsilanyl-phenylamino)-nicotinicacid (7.6 g, 21.3 mmol) in dichloromethane (100 mL) and DMF (1 mL) wasadded oxalyl chloride (9.1 mL, 106.4 mmol) dropwise over 20 minutes. Thereaction mixture was stirred at reflux for 18 hours and thenconcentrated in vacuo and the residue azeotroped with toluene. Theresultant residue was taken up in cold (0° C.) methanol (100 mL). Theresultant solution was heated at reflux for 1 hour, then cooled to roomtemperature and filtered. The precipitate was washed with cold methanoland dried under vacuum at 45° C. to give the title compound as a yellowsolid (7.3 g, 92%). LCMS (method B): R_(T)=5.38 min, [M+H]⁺=371.

Step 3:6-Cyano-5-fluoro-2-(2-fluoro-4-trimethylsilanyl-phenylamino)-nicotinicacid methyl ester

A degassed suspension of6-chloro-5-fluoro-2-(2-fluoro-4-trimethylsilanyl-phenylamino)-nicotinicacid methyl ester (7.8 g, 21.2 mmol), zinc (II) cyanide (1.84 g, 15.6mmol), and Pd(PPh₃)₄ (2.43 g, 2.12 mmol) in DMF (40 mL) was subjected tomicrowave irradiation at 150° C. for 15 minutes. The reaction mixturewas filtered through Celite® and the filtrate diluted with ethylacetate. The organic phase was washed twice with water and once withbrine, dried (Na₂SO₄), filtered and concentrated in vacuo. The resultantresidue was triturated with diethyl ether and pentane, and then driedunder vacuum to afford the title compound as a yellow solid (6.9 g,91%). LCMS (method B): R_(T)=4.99 min, [M+H]⁺=362.

Step 4:6-Aminomethyl-5-fluoro-2-(2-fluoro-4-trimethylsilanyl-phenylamino)-nicotinicacid methyl ester

To a suspension of6-cyano-5-fluoro-2-(2-fluoro-4-trimethylsilanyl-phenylamino)-nicotinicacid methyl ester (5.7 g, 15.8 mmol) in methanol (130 mL) was addedcobalt (II) chloride (7.5 g, 31.6 mmol). The reaction mixture wasstirred for 10 minutes, then cooled to 0° C. and sodium borohydride (6.0g, 158 mmol) was added in small portions over 30 minutes. The reactionmixture was stirred at 0° C. for 15 minutes and then at room temperaturefor 1 hour. The reaction was quenched by addition of concentratedhydrochloric acid (20 mL) and the mixture stirred for 15 minutes. Thereaction mixture was filtered to remove a white solid, which was washedwith dichloromethane, and the filtrate was concentrated under reducedpressure. The resultant residue was dissolved in ethyl acetate andwashed with a saturated solution of sodium bicarbonate, followed bywater then brine. The organic phase was isolated, dried (Na₂SO₄),filtered and concentrated in vacuo to afford the title compound as abrown solid (2.0 g, 34%). LCMS (method B): R_(T)=2.77 min, [M+H]⁺=366.

Step 5:5-Fluoro-2-(2-fluoro-4-trimethylsilanyl-phenylamino)-6-formylaminomethyl-nicotinicacid methyl ester

To a solution of6-aminomethyl-5-fluoro-2-(2-fluoro-4-trimethylsilanyl-phenylamino)-nicotinicacid methyl ester (2.0 g, 5.5 mmol) in formic acid (30 mL) at 0° C. wasadded acetic anhydride (6 mL). The reaction mixture was stirred atambient temperature for 2 hours. The reaction mixture was concentratedin vacuo and the resultant residue azeotroped with toluene, thendissolved in dichloromethane. This organic layer was washed with asaturated aqueous solution of sodium bicarbonate, followed by brine,dried (Na₂SO₄), filtered and concentrated in vacuo to afford the titlecompound as a dark brown solid (2.1 g, 100%). LCMS (method B):R_(T)=4.36 min, [M+H]⁺=394.

5-(4-Bromo-2-fluoro-phenylamino)-8-fluoro-imidazo[1,5-a]pyridine-6-carboxylicacid methyl ester

Step 1:2-(4-Bromo-2-fluoro-phenylamino)-5-fluoro-6-formylaminomethyl-nicotinicacid methyl ester

To a solution of5-fluoro-2-(2-fluoro-4-trimethylsilanyl-phenylamino)-6-formylaminomethyl-nicotinicacid methyl ester (2.6 g, 6.6 mmol) in dichloromethane (65 mL) at −30°C. was added NBS (1.2 g, 6.6 mmol). The reaction mixture was stirred at−30° C. for 1.5 hours, and then concentrated under reduced pressure Theresultant residue was taken up in ethyl acetate and this organicsolution was washed with a saturated aqueous solution of sodiumbicarbonate, followed by brine, dried (Na₂SO₄), filtered and evaporatedin vacuo to afford the title compound as a brown solid (2.49 g, 95%).LCMS (method B): R_(T)=3.79 min, [M+H]⁺=400/402.

Step 2:5-(4-Bromo-2-fluoro-phenylamino)-8-fluoro-imidazo[1,5-a]pyridine-6-carboxylicacid methyl ester

To a suspension of2-(4-bromo-2-fluoro-phenylamino)-5-fluoro-6-formylaminomethyl-nicotinicacid methyl ester (2.49 g, 6.2 mmol) in toluene (60 mL) was addedphosphorous oxychloride (0.65 mL, 7.0 mmol). The reaction mixture washeated to 90° C. and stirred for 1.5 hour before cooling to roomtemperature and concentrating in vacuo. The resultant residue wasdissolved in ethyl acetate and washed with water followed by a saturatedaqueous solution of sodium bicarbonate and then brine. The organic phasewas isolated, dried (MgSO₄), filtered and concentrated in vacuo. Theresultant residue was subjected to flash chromatography (Si-PPC,gradient 0% to 100%, ether in hexane) to afford the title compound as ayellow solid (692 mg, 29%). LCMS (method B): R_(T)=3.97 min,[M+H]⁺=382/384.

8-Fluoro-5-(2-fluoro-4-iodo-phenylamino)-imidazo[1,5-a]pyridine-6-carboxylicacid

Step 1:5-Fluoro-2-(2-fluoro-4-iodo-phenylamino)-6-formylaminomethyl-nicotinicacid methyl ester

To a solution of5-fluoro-2-(2-fluoro-4-trimethylsilanyl-phenylamino)-6-formylaminomethyl-nicotinicacid methyl ester (2.4 g, 6.1 mmol) in dichloromethane (15 mL) at 0° C.was added ICI (2.0 g, 12.2 mmol). The mixture was stirred at 0° C. for0.5 hour, then quenched with water, washed with a saturated solution ofsodium sulphite followed by brine, dried (Na₂SO₄), filtered andevaporated in vacuo to afford the title compound as a brown solid (2.7g, 98%). LCMS (method B): R_(T)=3.81 min, [M+H]⁺=448.

Step 2:8-Fluoro-5-(2-fluoro-4-iodo-phenylamino)-imidazo[1,5-a]pyridine-6-carboxylicacid methyl ester

To a suspension of5-fluoro-2-(2-fluoro-4-iodo-phenylamino)-6-formylaminomethyl-nicotinieacid methyl ester (2.7 g, 6.2 mmol) in toluene (20 mL) was addedphosphorous oxychloride (1.1 mL, 12.2 mmol). The reaction mixture washeated at 95° C. for 30 minutes. The reaction mixture was cooled to roomtemperature and then concentrated in vacuo. The resultant residue wasdissolved in ethyl acetate and washed with water followed by a saturatedaqueous solution of sodium bicarbonate, then brine. The organic phasewas isolated, dried (MgSO₄), filtered and concentrated in vacuo. Theresultant residue was subjected to flash chromatography (Si-PPC,gradient 0% to 50%, ethyl acetate in hexane) to afford the titlecompound as a yellow solid (1.0 g, 39%). LCMS (method B): R_(T)=3.97min, [M+H]⁺=430.

Step 3:8-Fluoro-5-(2-fluoro-4-iodo-phenylamino)-imidazo[1,5-a]pyridine-6-carboxylicacid

To a solution of8-fluoro-5-(2-fluoro-4-iodo-phenylamino)-imidazo[1,5-a]pyridine-6-carboxylicacid methyl ester (500 mg, 1.17 mmol) in IMS (10 mL) was added sodiumhydroxide (1.75 mL, 1M aqueous solution, 1.75 mmol), the reactionmixture heated at 65° C. for 45 min. The reaction mixture wasconcentrated in vacuo and the residue taken up in water. 1N HCl wasadded to adjust to pH 1. The precipitate formed was filtered off anddried in vacuo to give the title compound (435 mg, 90%). LCMS (methodB): R_(T)=3.47 min, [M+H]⁺=416.

Synthesis of Azaimidazo[1,5-a]Pyridines5-(2-Fluoro-4-iodo-phenylamino)-imidazo[1,5-a]pyrazine-6-carboxylic acidmethyl ester

Step 1: 3,5-Dichloro-pyrazine-2-carboxylic acid

To a solution of diisopropylamine (13.0 mL, 92.6 mmol, 2.3 eq.) inanhydrous THF (300 mL) at −78° C. under N₂ was added dropwise a solutionof 1.6 M nBuLi in hexanes (57.9 mL, 92.6 mmol, 2.3 eq.). After 1 hour asolution of 2,6-dichloropyrazine in anhydrous THF (6.0 g, 40.3 mmol) wasadded dropwise over 30 minutes. After stirring at −78° C. for 1 hour,the reaction mixture was poured onto crushed dry ice (solid carbondioxide), and the reaction mixture was stirred at ambient temperaturefor 16 hours. The mixture was then diluted with water (100 mL) andwashed with ethyl acetate (3×100 mL). The aqueous layer was cooled to 0°C., acidified with 2N HCl until pH ˜2, and extracted with ethyl acetate(3×100 mL). The combined organic extracts were dried (Na₂SO₄), filteredand evaporated in vacuo. The resultant crude was purified by columnchromatography (Si-PPC, gradient 0% to 50%, methanol in dichloromethane)to give the desired product as a beige solid (3.16 g, 40.6%). ¹H NMR(CDCl₃, 400 MHz) δ ppm 8.60 (s, 1H).

Step 2:5-Chloro-3-(2-fluoro-4-trimethylsilanyl-phenylamino)-pyrazine-2-carboxylicacid

To a solution of 2-fluoro-4-trimethylsilanyl-phenylamine (3.8 g, 20.7mmol, 2.0 eq) in anhydrous THF (150 mL) at −78° C. under N₂ was addeddropwise a solution of 1.0 M LHMDS in THF (33.2 mL, 30 mmol, 3.2 eq)over 20 minutes. After 1 hour at −78° C., a solution of3,5-dichloro-pyrazine-2-carboxylic acid (2.0 g, 10.3 mmol) in anhydrousTHF (30 mL) was added. The mixture was stirred at −78° C. for 30minutes, and then stirred at ambient temperature for 18 hours. Themixture was quenched with water and the pH adjusted to pH 2 by theaddition of 2 N HCl. The reaction mixture was extracted with ethylacetate, and the organic layer washed with water and brine, then dried(Na₂SO₄), filtered and evaporated in vacuo. The resultant residue waspurified by column chromotagraphy (Si-PPC, gradient 20 to 50% ethylacetate in hexane, followed by 0% to 30%, methanol in dichloromethane)to give the desired compound as a yellow solid (2.95 g, 83.8%). ¹H NMR(CDCl₃, 400 MHz) δ ppm 10.41 (s, 1H), 8.28 (t, J=7.79 Hz, 1H), 7.93 (s,1H), 7.40-7.23 (m, 2H), 0.27 (s, 9H).

Step. 3:5-Chloro-3-(2-fluoro-4-trimethylsilanyl-phenylamino)-pyrazine-2-carboxylicacid methyl ester

To a solution of5-chloro-3-(2-fluoro-4-trimethylsilanyl-phenylamino)-pyrazine-2-carboxylicacid (2.95 g, 8.68 mmol) in methanol (50 mL) and toluene (100 mL) at 0°C. under N₂ was added a solution of 2M trimethylsilyldiazomethane inhexanes (9.55 mL, 19.0 mmol, 2.2 eq.), and the reaction mixture wasstirred at ambient temperature for 30 minutes. The reaction mixture wasdiluted with ethyl acetate. The organic layer was washed with asaturated aqueous solution of sodium bicarbonate, water and brine, thendried (Na₂SO₄), filtered and evaporated in vacuo. The resultant residuewas purified by column chromotagraphy (Si-PPC, gradient 0 to 50% ethylacetate in hexane) to give the desired compound as a yellow solid (2.18g, 71.1%). ¹H NMR (CDCl₃, 400 MHz) δ ppm 10.54 (s, 1H), 8.36 (t, J=7.86Hz, 1H), 8.06 (s, 1H), 7.34-7.26 (m, 2H), 4.05 (s, 3H), 0.28 (s, 9H);LCMS (method D1) R_(T)=1.38 min, [M+H]⁺=354.

Step 4:5-Cyano-3-(2-fluoro-4-trimethylsilanyl-phenylamino)-pyrazine-2-carboxylicacid methyl ester

A degassed suspension of5-chloro-3-(2-fluoro-4-trimethylsilanyl-phenylamino)-pyrazine-2-carboxylicacid methyl ester (1.35 g, 3.82 mmol), zinc (II) cyanide (492.8 mg, 4.2mmol, 1.1 eq.), and Pd(PPh₃)₄ (551.0 mg, 0.48 mmol, 0.12 eq.) inanhydrous dimethylformamide (30 mL) was subjected to microwaveirradiation at 150° C. for 18 minutes. The reaction mixture was pouredinto ethyl acetate and then filtered through a pad of Celite®. The padwas rinsed well with ethyl acetate (2×). The combined filtrates werewashed with 50% brine (2×) and brine (1×), dried (Na₂SO₄), filtered andconcentrated in vacuo. The crude residue was purified by columnchromotagraphy (Si-PPC, gradient 0 to 30% ethyl acetate in hexane) togive a brown oil. Trituration with MeOH afforded the desired compound asan orange solid (1.31 g, 99.8%). ¹H NMR (CDCl₃, 400 MHz) δ ppm 10.56 (s,1H), 8.36 (s, 1H), 8.29 (t, J=7.82 Hz, 1H), 7.37-7.27 (m, 2H), 4.10 (s,3H), 0.29 (s, 9H); LCMS (method D1): R_(T)=1.28 min, [M+H]⁺=345.

Step 5:5-Aminomethyl-3-(2-fluoro-4-trimethylsilanyl-phenylamino)-pyrazine-2-carboxylicacid methyl ester

To a solution of5-cyano-3-(2-fluoro-4-trimethylsilanyl-phenylamino)-pyrazine-2-carboxylicacid methyl ester (600 mg, 1.74 mmol) in concentrated glacial aceticacid (12 mL) was added 10% Pd on carbon (120 mg). The reaction mixturewas evacuated with vacuum and purged with H₂ (3×), then stirred under anatmosphere of H₂ for 3.5 hours. The reaction mixture was then filteredthrough a pad of Celite®. The filtrate was concentrated in vacuo to givethe desired product as the HOAc salt. LCMS (method C): R_(T)=2.51 min,[M+H]⁺=349.

Step 6:3-(2-Fluoro-4-trimethylsilanyl-phenylamino)-5-formylaminomethyl-pyrazine-2-carboxylicacid methyl ester

A solution of5-aminomethyl-3-(2-fluoro-4-trimethylsilanyl-phenylamino)-pyrazine-2-carboxylicacid methyl ester (800 mg, 2.30 mmol) from above in formic acid (12 mL)and acetic anhydride (4 mL) was stirred at ambient temperature under N₂for 1.5 hour. The reaction mixture was concentrated in vacuo, and theresidue was azeotroped with toluene. The resultant residue was dilutedwith ethyl acetate. The organic layer was washed with saturated aqueoussolution of sodium bicarbonate, water and brine, dried (Na₂SO₄),filtered and concentrated in vacuo to afford the title compound as ayellow foam (850 mg, 98.3%). LCMS (method D1): R_(T)=1.09 min,[M+H]⁺=377.

Step 7:3-(2-Fluoro-4-iodo-phenylamino)-5-formylaminomethyl-pyrazine-2-carboxylicacid methyl ester

To a cold (0° C.) solution of3-(2-fluoro-4-trimethylsilanyl-phenylamino)-5-formylaminomethyl-pyrazine-2-carboxylicacid methyl ester (480 mg, 1.28 mmol) in dichloromethane (13 mL) underN₂ was added dropwise a solution of 1M iodine monochloride indichloromethane (3.0 mL, 3.0 mmol, 2.4 eq), and the mixture was stirredat 0° C. for 1.5 hour. The reaction was quenched by addition of asaturated aqueous solution of sodium thiosulfate (3 mL). After stirringfor 10 minutes the reaction mixture was poured into ethyl acetate. Theorganic layer was washed with a saturated aqueous solution of sodiumbicarbonate, water and brine, dried (Na₂SO₄), filtered and evaporated invacuo to afford the desired product as a yellow solid (548 mg, 99%).LCMS (method C): R_(T)=2.65 min, [M+H]⁺=431.

Step 8:5-(2-Fluoro-4-iodo-phenylamino)-imidazo[1,5-a]pyrazine-6-carboxylic acidmethyl ester

To a suspension of3-(2-fluoro-4-iodo-phenylamino)-5-formylaminomethyl-pyrazine-2-carboxylicacid methyl ester (480 mg, 1.12 mmol) in toluene (18 mL) was addedphosphorous oxychloride (0.42 mL, 4.4 mmol, 4.0 eq.), and the reactionmixture was heated at 95° C. for 1 hour. The reaction mixture was cooledto RT and then quenched with a saturated aqueous solution of sodiumbicarbonate (2 mL). The resultant residue was dissolved in ethyl acetateand washed with water and brine. The organic phase was isolated, dried(Na₂SO₄), filtered and concentrated in vacuo. The resultant residue wassubjected to flash chromatography (Si-PPC, gradient 0% to 20%, methanolin ethyl acetate) to give a yellow oil. Crystallization fromdichloromethane ether hexane afforded the desired product as a yellowsolid (190 mg, 41.3%). LCMS (method C): R_(T)=2.45 min, [M+H]⁺=413.

5-(4-Bromo-2-fluoro-phenylamino)-imidazol[1,5-a]pyrazine-6-carboxylicacid methyl ester

Step 1:3-(4-Bromo-2-fluoro-phenylamino)-5-formylaminomethyl-pyrazine-2-carboxylicacid methyl ester

To a −30° C. solution of3-(2-fluoro-4-trimethylsilanyl-phenylamino)-5-formylaminomethyl-pyrazine-2-carboxylicacid methyl ester (1.84 g, 4.89 mmol) in dichloromethane (50 mL) underN₂ was added NBS (0.96 g, 5.38 mmol, 1.1 eq.), and the reaction mixturewas stirred at −30° C. for 3 h. More NBS (0.96 g, 5.38 mmol, 1.1 eq.)was added, and the reaction mixture was allowed to stand at 0° C. for 18h. The reaction mixture was diluted with ethyl acetate (250 mL). Theorganic layer was washed with saturated aqueous solution of sodiumbicarbonate, water and brine, dried (Na₂SO₄), filtered and concentratedin vacuo. The crude material was triturated with methanol to afford thedesired product as a yellow solid (1.50 g, 80.1%). LCMS (method C):R_(T)=2.51 min, [M+H]⁺=383/384.

Step 2:5-(4-Bromo-2-fluoro-phenylamino)-imidazo[1,5-a]pyrazine-6-carboxylicacid methyl ester

To a suspension of3-(4-bromo-2-fluoro-phenylamino)-5-formylamino-methyl-pyrazine-2-carboxylicacid methyl ester (1.40 g, 3.65 mmol) in toluene (100 mL) was addedphosphorous oxychloride (1.50 mL, 16.1 mmol, 4.4 eq.), and the reactionmixture was heated at 95° C. under N₂ for 1 hour. The reaction mixturewas cooled to RT and then quenched with saturated aqueous solution ofsodium bicarbonate (20 mL). The resultant residue was dissolved in ethylacetate and washed with water and brine. The organic phase was isolated,dried (Na₂SO₄), filtered and concentrated in vacuo. The resultantresidue was subjected to flash chromatography (Si-PPC, gradient 70 to100% ethyl acetate in hexane, followed by 0% to 2% methanol in ethylacetate) to give an orange oil. Crystallization from ethyl acetatehexane afforded the desired product as an orange solid (1.26 g, 94.3%).LCMS (method D1): R_(T)=0.86 min, [M+H]⁺=366/367.

5-(2-Fluoro-4-iodophenylamino)imidazo[1,5-a]pyrazine-6-carboxamide

To a solution of5-(2-fluoro-4-iodo-phenylamino)-imidazo[1,5-a]pyrazine-6-carboxylic acid(64.0 mg, 0.16 mmol) in anhydrous THF (3.6 mL) was added HOBt (56.5 mg,0.42 mmol, 2.6 eq), DIPEA (0.073 mL, 0.42 mmol, 2.6 mmol), and EDCI(67.8 mg, 0.35 mmol, 2.2 eq), and the reaction mixture was stirred atroom temperature under N₂ for 2 h. Concentrated aqueous ammoniumhydroxide solution (0.50 mL) was added and the reaction mixture wasstirred at room temperature for 20 h. The reaction mixture was dilutedwith ethyl acetate (50 mL) and washed with a saturated aqueous solutionof ammonium chloride, water and brine. The organic layer was isolatedand dried (Na₂SO₄), filtered, and concentrated in vacuo. The resultantresidue was subjected to flash chromatography (Si-PPC, gradient 0 to 20%methanol in dichloromethane) to give an oil. Crystallization from DCMether hexane afforded the title compound as a beige solid (9.9 mg,16.0%). ¹H NMR (MeOD, 400 MHz) δppm 8.74 (s, 1H), 7.86 (s, 1H), 7.79 (s,1H), 7.62 (dd, J=10.4 Hz, 2.0 Hz, 1H), 7.48 (d, J=8.4 Hz, 1H), 6.59 (t,J=8.4 Hz, 1H); LCMS (method D1): R_(T)=0.84 min, [M+H]⁺=398.

Example 55-(2-Fluoro-4-iodophenylamino)-imidazo[1,5-a]pyridine-6-carboxylic acid(2-hydroxyethoxy)-amide

Step 1, Method A:5-(2-Fluoro-4-iodophenylamino)-imidazo[1,5-a]pyridine-6-carboxylic acid(2-vinyloxyethoxy)-amide

To a solution of5-(2-fluoro-4-iodophenylamino)-imidazo[1,5-a]pyridine-6-carboxylic acid(2.10 g, 5.29 mmol) and O-(2-vinyloxyethyl)-hydroxylamine (0.87 g, 8.46mmol) in DMF (30 mL) was added EDCI hydrochloride (1.31 g, 6.90 mmol),HOBt (0.93 g, 6.90 mmol) and DIPEA (1.17 mL, 6.90 mmol). The reactionmixture was stirred at room temperature for 5 hours before beingconcentrated in vacuo. The resultant residue was dissolved in 1:1tert-butylmethylether:ethyl acetate (20 mL) and aqueous saturated sodiumhydrogen carbonate solution (20 mL) was added. The resultant mixture wassonicated until a precipitate formed, the precipitate was collected byfiltration and dried in vacuo at 45° C. to yield the title compound as atan solid (1.55 g, 60%). LCMS (Method B): R_(T)=2.80 min, M+H⁺=483.

Step 1, Method B:5-(2-Fluoro-4-iodophenylamino)-imidazo[1,5-a]pyridine-6-carboxylic acid(2-vinyloxyethoxy)-amide

To a solution of5-(2-fluoro-4-iodophenylamino)imidazo[1,5-a]pyridine-6-carboxylic acidmethyl ester (1.5 g, 3.64 mmol) and O-(2-vinyloxyethyl)hydroxylamine(749 mg, 7.28 mmol) in THF (30 mL) at 0° C. was added lithiumbis(trimethylsilyl)amide as a solution in THF (18 mL, 1M, 18 mmol) over5 minutes. The reaction mixture was stirred at −0° C. for 1 hour beforebeing quenched with saturated aqueous ammonium chloride. Volatilesolvents were removed in vacuo and then diethyl ether (10 mL) and ethylacetate (20 mL) added. The resultant mixture was sonicated causing aprecipitate to form which was filtered off to give the title compound asa yellow solid (1.07 g, 61%). LCMS (Method B): R_(T)=2.79 min, M+H⁺=483.

Step 1, Method C:5-(2-Fluoro-4-iodophenylamino)-imidazo[1,5-a]pyridine-6-carboxylic acid(2-vinyloxyethoxy)-amide

To a mechanically stirred solution of5-(2-fluoro-4-iodophenylamino)imidazo[1,5-a]pyridine-6-carboxylic acidmethyl ester (82.17 g, 0.2 mol) and O-(2-vinyloxyethyl)hydroxylamine(40.73 g, 0.382 mol) in dry THF (1.27 L) at 5° C. under N₂ atmosphere,was added lithium bis(trimethylsilyl)amide as a solution in THF (1 L, 1M, 1 mol) over 1 hr, maintaining the temperature below 10° C. Thereaction mixture was stirred at 0-5° C. for 20 minutes before beingquenched with addition water (200 ml) and saturated saline (350 mL).Volatile solvents were removed in vacuo and the residue diluted withwater (1.5 L) and extracted 2-methyl tetrahydrofuran (3×1 L). Theorganic layers were washed water (500 mL), saturated saline (500 mL),dried (Na₂CO₃) and absorbed onto silica gel (200 g) and purified onsilica gel (400 g) using ethyl acetate as eluent. The resultant crudeproduct was triturated with tert-butyl methyl ether (400 mL) to yieldthe title compound as a brown solid (58.36 g, 60%). LCMS (Method B):R_(T)=2.79 min, [M+H]⁺=483.

Step 2, Method A:5-(2-fluoro-4-iodophenylamino)-imidazo[1,5-a]pyridine-6-carboxylic acid(2-hydroxyethoxy)-amide

To a suspension of5-(2-fluoro-4-iodophenylamino)-imidazo[1,5-a]pyridine-6-carboxylic acid(2-vinyloxyethoxy)-amide (2.87 g, 5.95 mmol) in methanol (45 mL) wasadded aqueous hydrochloric acid (11.9 mL, 1M, 11.9 mmol). The reactionmixture was stiffed at room temperature for 45 minutes during which timethe solids dissolved. The reaction mixture was concentrated in vacuo toremove the methanol. The resultant solution was diluted with 1:1tert-butylmethylether:ethyl acetate (20 mL) and aqueous saturated sodiumhydrogen carbonate solution (20 mL) added. The resultant mixture wassonicated until a precipitate formed and the precipitate was collectedby filtration and dried in vacuo at 45° C. to yield the title compoundas a yellow solid (2.5 g, 92%). LCMS (Method A): R_(T)=5.58 min,M+H⁺=457. ¹H NMR (DMSO-d₆, 400 MHz) 8.05 (1 H, s), 7.58 (1 H, dd,J=10.69, 1.92 Hz), 7.43 (1 H, s), 7.39 (1 H, d, J=9.33 Hz), 7.31-7.28 (1H, m), 6.89 (1 H, d, J=9.31 Hz), 6.34 (1 H, t, J=8.68 Hz), 4.64 (1 H,s), 3.64 (2 H, t, J=4.78 Hz), 3.46 (2 H, m).

Step 2, Method B:5-(2-Fluoro-4-iodophenylamino)-imidazo[1,5-a]pyridine-6-carboxylic acid(2-hydroxyethoxy)-amide

To a suspension of5-(2-fluoro-4-iodophenylamino)-imidazo[1,5-a]pyridine-6-carboxylic acid(2-vinyloxyethoxy)-amide (58.36 g, 0.12 mol) in methanol (600 mL) wasadded aqueous hydrochloric acid (242 mL, 1M, 0.242 mol). The reactionmixture was stirred and warmed to 45° C. for 1 hr during which time thesolids dissolved. The reaction mixture was then cooled to roomtemperature, and concentrated in vacuo to remove the methanol. Theresultant residue was treated with aqueous saturated sodium hydrogencarbonate and stirred at room temperature for 1 hr before collectingcrude product by filtration, and drying at 55° C. over phosphorus (V)oxide under vacuum for 24 hr. The crude product was crystallized fromIPA:H₂O (1:1, v/v) (800 mL) with slow cooling and mechanical stirring.The product was collected by filtration and washed cold IPA:H₂O (1:1,v/v) (100 mL) before being dried in vacuo at 55° C. to yield the titlecompound as a light brown solid (50.2 g, 90%). LCMS (Method A):R_(T)=5.58 min, [M+H]⁺=457. ¹H NMR (DMSO-d₆, 400 MHz) 8.05 (1 H, s),7.58 (1 H, dd, J=10.69, 1.92 Hz), 7.43 (1 H, s), 7.39 (1 H, d, J=9.33Hz), 7.31-7.28 (1 H, m), 6.89 (1 H, d, J=9.31 Hz), 6.34 (1 H, t, J=8.68Hz), 4.64 (1 H, s), 3.64 (2 H, t, J=4.78 Hz), 3.46 (2 H, m).

Example 65-(2-Fluoro-4-iodo-phenylamino)-imidazo[1,5-a]pyridine-6-carboxylic acid((R)-2,3-dihydroxy-propoxy)-amide

Step 1:5-(2-Fluoro-4-iodo-phenylamino)-imidazo[1,5-a]pyridine-6-carboxylic acid((S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-amide

To a solution of5-(2-fluoro-4-iodo-phenylamino)-imidazo[1,5-a]pyridine-6-carboxylic acid(326 mg, 0.82 mmol) in THF (4.1 ml) was addedO—((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-hydroxylamine (362 mg,2.46 mmol), DIPEA (1.26 ml, 7.4 mmol), HOBt (327 mg, 2.46 mmol) and EDCI(471 mg, 2.46 mmol), the mixture stirred for 18 hours at ambienttemperature. The reaction mixture was diluted with ethyl acetate andwashed with a saturated aqueous solution of sodium bicarbonate followedby water and then brine. The organic phase was isolated, dried (Na₂SO₄),filtered and concentrated in vacuo. Purification of the resultantresidue by flash chromatography (Si-PPC, gradient 0% to 10%, methanol indichloromethane) afforded the title compound as a pale yellow solid (364mg, 84%). LCMS (method B): R_(T)=2.58 min, [M+H]⁺=527.

Step 2:5-(2-Fluoro-4-iodo-phenylamino)-imidazo[1,5-a]pyridine-6-carboxylic acid((R)-2,3-dihydroxy-propoxy)-amide

A solution of5-(2-fluoro-4-iodo-phenylamino)-imidazo[1,5-a]pyridine-6-carboxylic acid((S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-amide (364 mg, 0.7 mmol) inmethanol (0.5 ml) and dichloromethane (0.5 ml) was loaded onto an SCX-2cartridge. The cartridge was flushed with methanol and the desiredproduct was eluted using a 2M solution of ammonia in methanol. Theappropriate fractions were combined and concentrated under reducedpressure and the residue was azeotroped with dichloromethane.Purification of the resultant residue by flash chromatography (Si-PPC,gradient 0% to 10%, methanol in dichloromethane) followed by preparativeHPLC (Gemini 5 micron C₆-Phenyl 250×21.20 mm column, 20 mmol Et₃N perlitre solvent, gradient acetonitrile/water, 5 to 98%, ramp time 25minutes) afforded the title compound as a yellow solid (77.6 mg, 23%).LCMS (method A): R_(T)=5.13 min, [M+H]⁺=487. ¹H NMR (DMSO-d₆): 8.01 (1H, s), 7.58 (1 H, dd, J=10.68, 1.92 Hz), 7.42 (1 H, s), 7.38 (1 H, d,J=9.34 Hz), 7.30 (1 H, dd, J=8.43, 1.82 Hz), 6.91 (1H, d, J=9.32 Hz),6.32 (1 H, t, J=8.68 Hz), 3.72-3.67 (1 H, m), 3.60-3.51 (2 H, m), 3.30(2H, d, J=4.94 Hz).

Example 75-(2-fluoro-4-iodo-phenylamino)-imidazo[1,5-a]pyridine-6-carboxylic acid((S)-2-hydroxy-propoxy)-amide

To a solution of5-(2-fluoro-4-iodo-phenylamino)-imidazo[1,5-a]pyridine-6-carboxylic acid(130 mg, 0.33 mmol) in THF (1.7 mL) was added (S)-1-aminooxy-propan-2-olhydrochloride (84 mg, 0.66 mmol), DIPEA (0.23 mL, 1.32 mmol), HOBt (88mg, 0.66 mmol) and EDCI (126 mg, 0.66 mmol). After 18 hours stirring atambient temperature, further (S)-1-aminooxy-propan-2-ol hydrochloride(84 mg, 0.66 mmol), DIPEA (0.23 mL, 1.32 mmol), HOBt (88 mg, 0.66 mmol)and EDCI (126 mg, 0.66 mmol) and THF (1.7 mL) were added. The reactionmixture was stirred at ambient temperature for a further 5 hours. Thereaction mixture was loaded onto an Isolute SCX-2 cartridge. Thecartridge was then washed with methanol and the desired compound waseluted using a 2M solution of ammonia in methanol. Appropriate fractionswere combined and concentrated under reduced pressure and the residueazeotroped with dichloromethane. The resultant residue was subjected toflash chromatography (Si-PPC, gradient 0 to 10%, methanol indichloromethane) to afford the title compound as a yellow solid (17 mg,11%). LCMS (method A): R_(T)=6.01 min, [M+H]⁺=471. ¹H NMR (DMSO-d₆):8.07 (1 H, s), 7.58 (1 H, dd, J=10.71, 1.92 Hz), 7.43 (1 H, s), 7.38 (1H, d, J=9.31 Hz), 7.31-7.28 (1 H, m), 6.89 (1 H, d, J=9.31 Hz), 6.35 (1H, t, J=8.68 Hz), 3.69-3.60 (1 H, m), 3.45-3.38 (2 H, m), 0.96 (3 H, d,J=6.35 Hz).

Example 85-(4-Bromo-2-fluorophenylamino)-imidazo[1,5-a]pyridine-6-carboxylic acid(2-hydroxyethoxy)-amide

Step 1:5-(4-Bromo-2-fluorophenylamino)-imidazo[1,5-a]pyridine-6-carboxylic acid(2-vinyloxyethoxy)-amide

To a solution of5-(4-Bromo-2-fluorophenylamino)-imidazo[1,5-a]pyridine-6-carboxylic acid(2.0 g, 5.7 mmol) and O-(2-vinyloxyethyl)-hydroxylamine (0.71 g, 6.8mmol) in DMF (44 mL) was added EDCI hydrochloride (1.42 g, 7.41 mmol),HOBt (1.0 g, 7.41 mmol) and DIPEA (0.97 mL, 5.69 mmol). The reactionmixture was stirred at room temperature for 3 hours before beingconcentrated in vacuo. The resultant residue was dissolved in 1:1diethylether:ethyl acetate (30 mL) and aqueous saturated sodium hydrogencarbonate solution (30 mL) was added. The resultant mixture wassonicated until a precipitate formed. The precipitate was collected byfiltration and washed with 1:1 diethylether:ethyl acetate to yield thetitle compound as a tan solid (1.33 g, 53%). LCMS (Method B): R_(T)=2.78min, M+H⁺=435/437.

Step 2:5-(4-Bromo-2-fluorophenylamino)-imidazo[1,5-a]pyridine-6-carboxylic acid(2-hydroxyethoxy)-amide

To a suspension of5-(4-Bromo-2-fluorophenylamino)-imidazo[1,5-a]pyridine-6-carboxylic acid(2-vinyloxyethoxy)-amide (1.33 g, 3.05 mmol) in methanol (40 mL) wasadded aqueous hydrochloric acid (6.7 mL, 1M, 6.7 mmol). The reactionmixture was stirred at room temperature for 30 minutes then concentratedin vacuo to remove the methanol. The resultant residue was dissolved in1:1 diethylether:ethyl acetate (30 mL) and aqueous saturated sodiumhydrogen carbonate solution (30 mL) added. The resultant mixture wassonicated until a precipitate formed, the precipitate collected byfiltration and washed with water then diethyl ether to yield the titlecompound as a yellow solid (1.12 g, 90%). LCMS (method A): R_(T)=5.22min, [M+H]⁺=409/411. ¹H NMR (DMSO-d₆, 400 MHz) 9.20 (1 H, s), 8.07 (1 H,s), 7.51 (1 H, dd, J=10.86, 2.22 Hz), 7.44 (1 H, s), 7.40 (1 H, d,J=9.33 Hz), 7.16 (1 H, ddd, J=8.61, 2.20, 1.07 Hz), 6.89 (1 H, d, J=9.31Hz), 6.50 (1 H, t, J=8.84 Hz), 4.63 (1 H, s), 3.65 (2 H, t, J=4.79 Hz),3.46 (3 H, s).

Example 95-(4-Bromo-2-fluoro-phenylamino)-imidazo[1,5-a]pyridine-6-carboxylicacid ((S)-2-hydroxy-propoxy)-amide

To a solution of5-(4-bromo-2-fluoro-phenylamino)-imidazo[1,5-a]pyridine-6-carboxylicacid (271 mg, 0.77 mmol) in dioxane (3.9 mL) was added HOBT (306 mg, 2.3mmol) and EDCI (442 mg, 2.3 mmol). The reaction mixture was stirred atambient temperature for 30 minutes then (S)-1-aminooxy-propan-2-olhydrochloride (294 mg, 2.3 mmol) and DIPEA (1.2 mL, 6.9 mmol) wereadded, the mixture was then stirred for 60 hours at ambient temperature.The reaction mixture was diluted with ethyl acetate then washed with asaturated aqueous solution of sodium bicarbonate followed by water andbrine. The organic phase was isolated, dried (Na₂SO₄), filtered andconcentrated in vacuo. The resultant residue was subjected to flashchromatography (Si-PPC, gradient 0 to 100%, ethyl acetate indichloromethane, then gradient 0 to 10%, methanol in dichloromethane) toafford the title compound as a green/yellow solid (80 mg, 25%). LCMS(method A): R_(T)=5.71 min, [M+H]⁺=423/425. ¹H NMR (DMSO-d₆): 8.10 (1 H,s), 7.51 (1 H, dd, J=10.87, 2.22 Hz), 7.43 (1 H, s), 7.39 (1 H, d,J=9.31 Hz), 7.18-7.14 (1 H, m), 6.88 (1 H, d, J=9.31 Hz), 6.51 (1 H, t,J=8.85 Hz), 4.69 (1 H, s), 3.68-3.59 (1 H, m), 3.42 (2 H, d, J=5.81 Hz),0.95 (3 H, d, J=6.35 Hz).

Example 105-(4-Bromo-2-fluoro-phenylamino)-8-fluoro-imidazo[1,5-a]pyridine-6-carboxylicacid ((S)-2-hydroxy-propoxy)-amide

To a solution of5-(4-bromo-2-fluoro-phenylamino)-8-fluoro-imidazo[1,5-a]pyridine-6-carboxylicacid methyl ester (351 mg, 0.92 mmol) in IMS (10 mL) was added sodiumhydroxide (1.0 mL, 1M aqueous solution, 1.0 mmol). The reaction mixturewas heated at 65° C. for 1 hour, and then concentrated in vacuo. Theresultant residue was azeotroped with toluene and then suspended indioxane. EDCI (353 mg, 1.84 mmol) and HOBt (248 mg, 1.84 mmol) wereadded and the mixture was stirred at room temperature for 20 minutes.(S)-1-Aminooxy-propan-2-ol hydrochloride (235 mg, 1.84 mmol) and DIPEA(0.63 mL, 3.68 mmol) were added and the resultant mixture was stirredfor 18 hours, before being concentrated under reduced pressure. Theresultant residue was taken up in ethyl acetate then washed with asaturated aqueous solution of sodium bicarbonate followed by water andbrine. The organic phase was isolated, dried (Na₂SO₄), filtered andconcentrated in vacuo. The resultant residue was subjected to flashchromatography (Si-PPC, gradient 0 to 10%, methanol in dichloromethane)to give a pale yellow solid (124 mg), which was further purified bypreparative HPLC (Gemini 5 micron C₁₈ 250×21.20 mm column, 0.1% formicacid, gradient acetonitrile/water, 5 to 85%, ramp time 15 minutes) toafford the title compound as an off-white solid (70 mg, 17%). LCMS(method A): R_(T)=7.83 min, [M+H]⁺=441/443. ¹H NMR (CDCl₃): 9.45 (1 H,s), 8.99 (1 H, s), 7.76 (1 H, d, J=2.95 Hz), 7.59 (1 H, s), 7.29 (1 H,dd, J=10.10, 2.16 Hz), 7.12 (1 H, d, J=8.52 Hz), 6.50 (1 H, d, J=10.18Hz), 6.41 (1 H, t, J=8.54 Hz), 4.03 (1 H, t, J=7.52 Hz), 3.94 (1 H, d,J=11.57 Hz), 3.70 (1 H, t, J=10.24 Hz), 1.14 (3 H, d, J=6.46 Hz).

Example 118-Fluoro-5-(2-fluoro-4-iodo-phenylamino)-imidazo[1,5-a]pyridine-6-carboxylicacid (2-hydroxy-ethoxy)-amide

Step 1:8-Fluoro-5-(2-fluoro-4-iodo-phenylamino)-imidazo[1,5-a]pyridine-6-carboxylicacid (2-vinyloxy-ethoxy)-amide

8-Fluoro-5-(2-fluoro-4-iodo-phenylamino)-imidazo[1,5-a]pyridine-6-carboxylicacid (0.20 g, 0.48 mmol), O-(2-vinyloxyethyl)-hydroxylamine (55 mg, 0.53mmol), EDCI (102 mg, 0.53 mmol), HOBt (72 mg, 0.53 mmol) and DIPEA (90μL, 0.53 mmol) were dissolved in DMF (10 mL) and the reaction mixturestirred at room temperature for 16 hours before being concentrated invacuo. The resultant residue was dissolved in ethyl acetate (10 mL),washed with aqueous saturated sodium bicarbonate solution (10 mL) andthe aqueous fraction extracted twice with ethyl acetate (2×10 mL). Thecombined organic fractions were washed with brine (20 mL), dried (MgSO₄)and concentrated in vacuo. The resultant residue was subjected to flashchromatography (SiO₂, gradient 0-10% methanol in DCM) to yield the titlecompound as a pale yellow solid (200 mg, 83%). LCMS (Method B):R_(T)=3.41 min, [M+H]⁺=501.

Step 2:8-Fluoro-5-(2-fluoro-4-iodo-phenylamino)-imidazo[1,5-a]pyridine-6-carboxylicacid (2-hydroxy-ethoxy)-amide

A solution of8-fluoro-5-(2-fluoro-4-iodo-phenylamino)-imidazo[1,5-a]pyridine-6-carboxylicacid (2-vinyloxy-ethoxy)-amide (200 mg, 0.39 mmol) in methanol (1 mL)was loaded onto an SCX-2 column. The column was washed with methanol (10mL) then the product was then eluted with ammonia in methanol (20 mL,2M), the appropriate fractions were concentrated in vacuo. The resultantresidue was subjected to reverse phase preperative HPLC (10-90%acetonitrile/water 0.1% formic acid, Phenominex gemini PhC6, 5 micron,250×20 mm). The resultant product was dissolved in ethyl acetate (5 mL)and washed with aqueous saturated sodium bicarbonate solution (10 mL).The aqueous fraction was extracted twice with ethyl acetate (2×10 mL)and the combined organics were washed with brine (20 mL), dried (MgSO₄)and concentrated in vacuo to yield the title compound as a white solid(88 mg, 39%). LCMS (Method A): R_(T)=7.71 min, [M+H]⁺=475. ¹H NMR(DMSO-d₆): 8.20 (1 H, s), 7.60 (1 H, s), 7.57 (1 H, dd, J=10.73, 1.96Hz), 7.26 (1 H, dd, J=8.43, 1.82 Hz), 6.82 (1 H, d, J=11.14 Hz), 6.30 (1H, t, J=8.71 Hz), 3.65 (2 H, t, J=4.77 Hz), 3.45 (2 H, t, J=4.68 Hz).

Example 128-Fluoro-5-(2-fluoro-4-iodo-phenylamino)-imidazo[1,5-a]pyridine-6-carboxylicacid ((R)-2,3-dihydroxy-propoxy)-amide

Step 1:8-Fluoro-5-(2-fluoro-4-iodo-phenylamino)-imidazo[1,5-a]pyridine-6-carboxylicacid ((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-amide

8-Fluoro-5-(2-fluoro-4-iodo-phenylamino)-imidazo[1,5-a]pyridine-6-carboxylicacid (235 mg, 0.57 mmol),O—(((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-hydroxylamine (92 mg,0.62 mmol), EDCI (120 mg, 0.62 mmol), HOBt (84 mg, 0.62 mmol) and DIPEA(0.1 mL, 0.62 mmol) were dissolved in DMF (10 mL) and the reactionmixture stirred at room temperature for 72 hours before beingconcentrated in vacuo. The resultant residue was dissolved in ethylacetate (10 mL), washed with aqueous saturated sodium bicarbonatesolution (10 mL) and the aqueous fraction extracted twice with ethylacetate (2×10 mL). The combined organic fractions were washed with brine(20 mL), dried with MgSO₄ and concentrated in vacuo. The resultantresidue was subjected to flash chromatography (SiO₂, gradient 0-10%methanol in DCM) to yield the title compound as a pale yellow solid (298mg, 97%). LCMS (Method B): R_(T)=3.34 min, [M+H]⁺=545.

Step 2:8-Fluoro-5-(2-fluoro-4-iodo-phenylamino)-imidazo[1,5-a]pyridine-6-carboxylicacid ((R)-2,3-dihydroxy-propoxy)-amide

To a solution of8-fluoro-5-(2-fluoro-4-iodo-phenylamino)-imidazo[1,5-a]pyridine-6-carboxylicacid ((R)-2,2-dimethyl-[1,3]-dioxolan-4-ylmethoxy)-amide (298 mg, 0.55mmol) in methanol (5 mL) was added hydrochloric acid in dioxane (2 mL,4N, 8.0 mmol). The reaction mixture was stirred at room temperature for1 hour then concentrated in vacuo. The resultant residue was dissolvedin ethyl acetate (5 mL), washed with aqueous saturated sodiumbicarbonate solution (10 mL) and the aqueous fraction extracted twicewith ethyl acetate (2×5 mL). The combined organic fractions were washedwith brine (10 mL), dried (MgSO₄) and concentrated in vacuo. Theresultant residue was subjected to reverse phase preperative HPLC(10-90% acetonitrile/water 0.1% formic acid, Phenominex gemini PhC6, 5micron, 250×20 mm). The resultant product was dissolved in ethyl acetate(5 mL) and washed with aqueous saturated sodium bicarbonate solution (10mL). The aqueous fraction was extracted twice with ethyl acetate (2×10mL) and the combined organics washed with brine (20 mL), dried (MgSO₄)and concentrated in vacuo to yield the title compound as a white solid(83 mg, 30%). LCMS (Method A): R_(T)=7.11 min, [M+H]⁺=505. ¹H NMR(DMSO-d₆): 11.63 (1 H, s), 8.97 (1 H, s), 8.22 (1 H, d, J=3.06 Hz), 7.61(1 H, s), 7.57 (1 H, dd, J=10.74, 1.93 Hz), 7.26 (1 H, d, J=8.50 Hz),6.82 (1 H, d, J=11.09 Hz), 6.32 (1 H, t, J=8.74 Hz), 3.72-3.65 (1 H, m),3.59-3.50 (2 H, m), 3.29 (2 H, m).

Example 138-Fluoro-5-(2-fluoro-4-iodo-phenylamino)-imidazo[1,5-a]pyridine-6-carboxylicacid ((S)-2-hydroxy-propoxy)-amide

A suspension of8-fluoro-5-(2-fluoro-4-iodo-phenylamino)-imidazo[1,5-a]pyridine-6-carboxylicacid (100 mg, 0.23 mmol), HATU (130 mg, 0.34 mmol), DIPEA (0.06 mL, 0.34mmol) and (S)-2-hydroxy-propoxy-amide hydrochloride (44 mg, 0.34 mmol)in THF (1 mL) was stirred at room temperature for 18 hours. The reactionmixture was partitioned between ethyl acetate (5 mL) and 1M HCl, theorganic layer was isolated and washed with saturated aqueous NaHCO₃ (2×5mL) and brine (2×5 mL), dried over Na₂SO₄, filtered and concentrated invacuo. The resultant residue was subjected to reverse-phase preparativeHPLC (Gemini 5 micron C₁₈ 250×21.20 mm column, 0.1% formic acid,gradient acetonitrile/water, 5 to 98%, ramp time 20 minutes) to affordthe title compound as a yellow solid (13 mg, 8%). LCMS (method A):R_(T)=8.13 min, [M+H]⁺=489. ¹H NMR (DMSO-d₆): 11.51 (1 H, broad), 8.95(1 H, broad), 8.25 (1 H, s), 7.60 (1 H, s), 7.55 (1 H, d, J=10.7 Hz),7.27 (1 H, d, J=8.4 Hz), 6.82 (1 H, d, J=11.1 Hz), 6.32 (1 H, t, J=8.8Hz), 4.66 (1 H, broad), 3.64 (1 H, m), 3.43 (2 H, d, J=5.8 Hz), 0.94 (3H, d, J=6.3 Hz).

Example 145-(2-Fluoro-4-methanesulfanyl-phenylamino)-imidazo[1,5-a]pyridine-6-carboxylicacid (2-hydroxy-ethoxy)-amide

Step 1:5-(2-Fluoro-4-methanesulfanyl-phenylamino)-imidazo[1,5-a]pyridine-6-carboxylicacid (2-vinyloxy-ethoxy)-amide

To a mixture of5-(2-fluoro-4-methanesulfanyl-phenylamino)-imidazo[1,5-a]pyridine-6-carboxylicacid (400 mg, 1.26 mmol), O-(2-vinyloxyethyl)-hydroxylamine (260 mg,2.52 mmol) and HOBt (221 mg, 1.64 mmol) in DMF (5 mL) was added EDCIhydrochloride (312 mg, 1.64 mmol), and DIPEA (0.285 mL, 1.64 mmol) andthe mixture stirred at room temperature for 20 hours. The products werepartitioned between ethyl acetate and saturated aqueous NaHCO₃. Theorganic layer was separated and washed with brine, then dried (Na₂SO₄),filtered and concentrated in vacuo to give the title compound (263 mg,52%). LCMS (Method B): R_(T) 2.64 [M+H]⁺403.

Step 2:5-(2-fluoro-4-methanesulfanyl-phenylamino)-imidazo[1,5-a]pyridine-6-carboxylicacid (2-hydroxy-ethoxy)-amide

To a solution5-(2-fluoro-4-methanesulfanyl-phenylamino)-imidazo[1,5-a]pyridine-6-carboxylicacid (2-vinyloxy-ethoxy)-amide (263 mg, 0.65 mmol) in methanol (10 mL)was added 1M hydrochloric acid (1 mL, 1 mmol.) and the mixture stirredat room temperature for 2 hours. The resultant mixture was concentratedin vacuo before being partitioned between saturated aqueous NaHCO₃ andethyl acetate. The organic layer was separated, washed with water, dried(Na₂SO₄), filtered and concentrated in vacuo. The resultant residue wastriturated with ethyl acetate and the solid collected by filtration wassubjected to flash chromatography (Si-PPC, gradient 0 to 10%, methanolin DCM) to afford the title compound as a tan solid (123 mg, 50%). LCMS(method A): R_(T)=5.15 min, [M+H]⁺=377. ¹H NMR (DMSO-d₆, 400 MHz) 11.54(1H, s), 9.39 (1 H, s), 7.93 (1 H, s), 7.39 (1 H, s), 7.32 (1 H, d,J=9.36 Hz), 7.16 (1 H, dd, J=11.86, 2.13 Hz), 6.93-6.88 (2 H, m), 6.57(1 H, t, J=8.65 Hz), 4.62 (1 H, s), 3.66 (2 H, t, J=4.85 Hz), 3.45 (2 H,t, J=4.77 Hz), 2.40 (3 H, s).

Example 155-(2-Fluoro-4-iodo-phenylamino)-imidazo[1,5-a]pyrazine-6-carboxylic acid(2-hydroxy-ethoxy)-amide

Step 1:5-(2-Fluoro-4-iodo-phenylamino)-imidazo[1,5-a]pyrazine-6-carboxylic acid

To a solution of5-(2-fluoro-4-iodo-phenylamino)-imidazo[1,5-a]pyrazine-6-carboxylic acidmethyl ester (140 mg, 0.34 mmol) in anhydrous 1,2-dichloroethane (2.5mL) was added trimethyltin hydroxide (215 mg, 1.19 mmol, 3.5 eq.). Thereaction mixture was heated at 85° C. for 1 hour and then cooled to RT.The reaction mixture was concentrated in vacuo, and the crude residuewas diluted with ethyl acetate. The organic layer was washed with 1N HCl(3×), water and brine, dried (Na₂SO₄), filtered and concentrated invacuo. Crystallization from dichloromethane ether hexane afforded thetitle compound as a yellow solid (132.1 mg, 97.7%). ¹H NMR (MeOD, 400MHz) δ ppm 8.76 (s, 1H), 7.92 (s, 1H), 7.86 (s, 1H), 7.64 (dd, J=10.13,1.84 Hz, 1H), 7.55-7.50 (m, 1H), 6.72 (t, J=8.49 Hz, 1H); LCMS (methodD1): R_(T)=0.77 min, [M+H]⁺=399.

Step 2:5-(2-Fluoro-4-iodo-phenylamino)-imidazo[1,5-a]pyrazine-6-carboxylic acid(2-vinyloxy-ethoxy)-amide

A mixture of5-(2-fluoro-4-iodo-phenylamino)-imidazo[1,5-a]pyrazine-6-carboxylic acid(110 mg, 0.28 mmol), O-(2-vinyloxy-ethyl)-hydroxylamine (45.6 mg, 0.44mmol, 1.6 eq.), HATU (157.6 mg, 0.41 mmol, 1.5 eq.), and DIPEA (96.0 μL,0.55 mmol, 2.0 eq.) in anhydrous DMF (4.2 mL) was stirred for 18 hoursunder N₂ at ambient temperature. The reaction mixture was diluted withethyl acetate and washed with a saturated aqueous solution of sodiumbicarbonate followed by water and brine. The organic phase was isolated,dried (Na₂SO₄), filtered and concentrated in vacuo. The resultantresidue was subjected to flash chromatography (Si-PPC, gradient 0% to15%, methanol in dichloromethane) to afford the desired product as ayellow solid (24 mg, 18%). LCMS (method D1): R_(T)=1.00 min, [M+H]⁺=484.

Step 3:5-(2-Fluoro-4-iodo-phenylamino)-imidazo[1,5-a]pyrazine-6-carboxylic acid(2-hydroxy-ethoxy)-amide

To a solution of5-(2-fluoro-4-iodo-phenylamino)-imidazo[1,5-a]pyrazine-6-carboxylic acid(2-vinyloxy-ethoxy)-amide (24.0 mg, 0.05 mmol) in methanol (0.5 mL) anddichloromethane (1.0 mL) was added 4M HCl in 1,4-dioxane (30 μL, 0.1mmol, 2.5 eq.), and the reaction was stirred at ambient temperatureunder N₂ for 2 h. The reaction mixture was concentrated in vacuo thenpoured into ethyl acetate. The organic layer was washed with a saturatedsolution of sodium bicarbonate, water, and brine. The organic phase wasisolated, dried (Na₂SO₄), filtered and concentrated in vacuo. Theresultant residue was subjected to flash chromatography (Si-PPC,gradient 0% to 25%, methanol in dichloromethane) to afford the titlecompound as yellow solid (11.6 mg, 51%). ¹H NMR (MeOD, 400 MHz) δ ppm8.74 (s, 1H), 7.87 (s, 1H), 7.84 (s, 1H), 7.62 (dd, J=10.20, 1.82 Hz,1H), 7.48 (d, J=8.41 Hz, 1H), 6.61 (t, J=8.53 Hz, 1H), 4.05 (t, J=4.80Hz, 2H), 3.78 (t, J=4.80 Hz, 2H)); LCMS (method E1): R_(T)=4.33 min,[M+H]⁺=458.

Example 165-(2-fluoro-4-iodo-phenylamino)-imidazo[1,5-a]pyrazine-6-carboxylic acid((S)-2-hydroxy-propoxy)-amide

To a solution of5-(2-fluoro-4-iodo-phenylamino)-imidazo[1,5-a]pyrazine-6-carboxylic acid(85 mg, 0.21 mmol) in anhydrous DMF (1.0 mL) was added(S)-1-aminooxy-propan-2-ol hydrochloride (32.7 mg, 0.26 mmol, 1.2 eq.),DIPEA (0.13 mL, 0.77 mmol, 3.6 eq.), HOBt (36.0 mg, 0.26 mmol, 1.2 eq.)and EDCI (51.2 mg, 0.26 mmol, 1.2 eq.), and the reaction mixture wasstirred at ambient temperature under N₂ for 16 hours. The reactionmixture was poured into ethyl acetate, and the organic layer was washedwith a saturated solution of sodium bicarbonate, 50% brine and brine.The organic phase was isolated, dried (Na₂SO₄), filtered andconcentrated in vacuo. The resultant residue was subjected to flashchromatography (Si-PPC, gradient 0% to 40%, methanol in ethyl acetate)to give an oil. Crystallization from dichloromethane ether hexaneafforded the title compound as a yellow solid (10.7 mg, 10.6%). ¹H NMR(MeOD, 400 MHz) δ ppm 8.76 (s, 1H), 7.92 (s, 1H), 7.86 (s, 1H), 7.64(dd, J=10.13, 1.84 Hz, 1H), 7.55-7.50 (m, 1H), 6.72 (t, J=8.49 Hz, 1H);LCMS (method E1): R_(T)=5.14 min, [M+H]⁺=472.

Example 175-(4-Cyclopropyl-2-fluoro-phenylamino)-imidazo[1,5-a]pyridine-6-carboxylicacid (2-hydroxy-ethoxy)-amide

Step 1:5-(4-Cyclopropyl-2-fluoro-phenylamino)-imidazo[1,5-a]pyridine-6-carboxylicacid (2-vinyloxy-ethoxy)-amide

To a mixture of5-(4-cyclopropyl-2-fluoro-phenylamino)-imidazo[1,5-a]pyridine-6-carboxylicacid (400 mg, 1.29 mmol), O-(2-vinyloxyethyl)-hydroxylamine (265 mg,2.57 mmol) and HOBt (225 mg, 1.67 mmol) in DMF (5 mL) was added EDCIhydrochloride (320 mg, 1.67 mmol), and DIPEA (0.290 mL, 1.67 mmol)before the reaction mixture was stirred at room temperature for 18hours. The products were partitioned between ethyl acetate and saturatedaqueous NaHCO₃, the organic layer separated and washed with brine thendried (Na₂SO₄), filtered and concentrated in vacuo. The resultantresidue was subjected to flash chromatography (Si-PPC, gradient 0-35%ethyl acetate in cylcohexane) to give the title compound (270 mg, 53%).LCMS (Method B): R_(T) 2.79 [M+H]⁺397.

Step 2:5-(4-Cyclopropyl-2-fluoro-phenylamino)-imidazo[1,5-a]pyridine-6-carboxylicacid (2-hydroxy-ethoxy)-amide

To a solution of5-(4-cyclopropyl-2-fluoro-phenylamino)-imidazo[1,5-a]pyridine-6-carboxylicacid (2-vinyloxy-ethoxy)-amide (270 mg, 0.681 mmol) in methanol (10 mL)was added 1M hydrochloric acid (2 mL, 2 mmol.) and the mixture stirredat room temperature for 2 hours. Solvent was removed in vacuo, and thensaturated aqueous NaHCO₃ added and the mixture extracted with ethylacetate. The organic layer was separated, dried (Na₂SO₄), filtered andconcentrated in vacuo. The resultant residue was triturated with TBMEand the solid collected by filtration to give the title compound as anoff-white solid (103 mg, 41%). LCMS (Method A): R_(T) 5.68 [M+H]⁺371. ¹HNMR (DMSO-d₆, 400 MHz) 7.81 (1 H, s), 7.37-7.34 (1 H, m), 7.27 (1 H, d,J=9.37 Hz), 6.95 (1 H, d, J=9.34 Hz), 6.91 (1 H, dd, J=12.49, 1.92 Hz),6.75 (1 H, dd, J=8.27, 1.96 Hz), 6.56-6.46 (1 H, m), 3.71-3.65 (2 H, m),3.48-3.43 (2 H, m), 1.89-1.80 (1 H, m), 0.91-0.85 (2 H, m), 0.65-0.57 (2H, m).

Example 18(R)—N-(2,3-Dihydroxypropoxy)-5-(2-fluoro-4-iodophenylamino)imidazo[1,5-a]pyrazine-6-carboxamide

Step 1:(R)—N-((2,2-Dimethyl-1,3-dioxolan-4-yl)methoxy)-5-(2-fluoro-4-iodophenylamino)imidazo[1,5-a]pyrazine-6-carboxamide

To a solution of5-(2-fluoro-4-iodo-phenylamino)-imidazo[1,5-a]pyrazine-6-carboxylic acid(100.0 mg, 0.25 mmol) in anhydrous DMF (2.5 mL) was added, in order,(R)-04(2,2-dimethyl-1,3-dioxolan-4-yl)methyphydroxylamine (40.7 mg, 0.28mmol, 1.1 eq.), HOBt (37.3 mg, 0.27 mmol, 1.1 eq.), EDCI (53.0 mg, 0.27mmol, 1.1 eq.), and N-methylmorpholine (0.1 mL, 0.91 mmol, 3.6 mmol).The reaction mixture was stirred at room temperature under N₂ for 3days. The reaction mixture was diluted with ethyl acetate, and theorganic layer was washed with a saturated solution of sodiumbicarbonate, water and brine. The organic phase was isolated, dried(Na₂SO₄), filtered and concentrated in vacuo. The resultant residue wassubjected to flash chromatography (Si-PPC, gradient 80% to 100%, ethylacetate in hexane, followed by gradient 0 to 20% methanol in ethylacetate) to give a yellow solid (72.6 mg, 54.8%). LCMS (method D1):R_(T)=0.97 min, [M+H]⁺=528.

Step 2:(R)—N-(2,3-Dihydroxypropoxy)-5-(2-fluoro-4-iodophenylamino)imidazo[1,5-a]pyrazine-6-carboxamide

To a heterogeneous mixture of(R)—N-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-5-(2-fluoro-4-iodophenylamino)imidazo[1,5-a]pyrazine-6-carboxamide(69.5 mg, 0.13 mmol) in anhydrous methanol (1.6 mL) was added 4M HCl in1,4-dioxane (0.13 mL, 0.5 mmol, 4.0 eq). The reaction mixture wasstirred at room temperature for 10 minutes. Solid sodium sulfate (200mg) was then added. The reaction mixture was absorbed onto silica andthen subjected to flash chromatography (Si-PPC, gradient 0% to 40%methanol in dichloromethane) to give the title compound as yellow foam(43.2 mg, 67.3%). ¹H NMR (DMSO-d₆, 400 MHz) δ ppm 11.90 (s, 1H), 10.30(s, 1H), 8.82 (s, 1H), 7.95 (s, 1H), 7.91 (s, 1H), 7.74 (d, J=9.6 Hz,1H), 7.44 (d, 8.4 Hz, 1H), 6.60 (t, J=8.4 Hz, 1H), 4.86 (d, J=4.4 Hz,1H), 4.55 (broad s, 1H), 3.99-3.91 (m, 1H), 3.79-3.69 (m, 2H), 3.39(broad s, 2H); LCMS (method E2): R_(T)=8.40 min, [M+H]⁺=488.

Example 19N-Ethoxy-5-(2-fluoro-4-iodophenylamino)imidazo[1,5-a]pyrazine-6-carboxamide

To a solution of5-(2-fluoro-4-iodo-phenylamino)-imidazo[1,5-a]pyrazine-6-carboxylic acidmethyl ester (165.0 mg, 0.40 mmol) and O-ethylhydroxylaminehydrochloride (78.1 mg, 0.80 mmol, 2.0 eq) in anhydrous THF (9.4 mL) at0° C. was added lithium hexamethyldisilazide (1M in THF, 1.2 mL, 1.2mmol, 3.0 eq). After stirring at room temperature for 16 h, additionalO-ethylhydroxylamine hydrochloride (234.3 mg, 2.40 mmol, 3.0 eq) andlithium hexamethyldisilazide (1M in THF, 3.6 mL, 3.6 mmol, 9.0 eq) wereadded at 0° C., and the reaction mixture was stirred at room temperaturefor 3 days. The reaction mixture was then quenched with saturatedaqueous solution of sodium bicarbonate (5 mL) and diluted with ethylacetate (50 mL). The organic layer was isolated and washed with waterand brine, dried (Na₂SO₄), filtered and concentrated in vacuo. Theresultant residue was subjected to flash chromatography (Si-PPC,gradient 45% to 100%, ethyl acetate in hexane, followed by gradient 0 to15% methanol in ethyl acetate) to give an oil. Crystallization from DCMether hexane afforded the title compound as a yellow solid (33.7 mg,19.1%). ¹H NMR (DMSO-d₆, 400 MHz) δ ppm 11.86 (s, 1H), 10.38 (s, 1H),8.82 (s, 1H), 7.94 (s, 1H), 7.92 (s, 1H), 7.73 (d, J=10.4 Hz, 1H), 7.44(d, 8.4 Hz, 1H), 6.57 (t, J=8.4 Hz, 1H), 3.90 (q, J=7.2 Hz, 2H), 1.18(t, J=6.8 Hz, 3H); LCMS (method D2): R_(T)=1.24 min, [M+H]⁺=442.

Example 20N-(Cyclopropylmethoxy)-5-(2-fluoro-4-iodophenylamino)imidazo[1,5-a]pyrazine-6-carboxamide

The title compound was prepared in an analogous fashion toN-ethoxy-5-(2-fluoro-4-iodophenylamino)imidazo[1,5-a]pyrazine-6-carboxamide,using O-(cyclopropylmethyl)-hydroxylamine hydrochloride as the startingmaterial. ¹H NMR (DMSO-d₆, 400 MHz) δ ppm 11.82 (s, 1H), 10.36 (s, 1H),8.82 (s, 1H), 7.95 (s, 1H), 7.91 (s, 1H), 7.73 (dd, J=10.4 Hz, 1.8 Hz,1H), 7.44 (d, 8.4 Hz, 1H), 6.58 (t, J=8.4 Hz, 1H), 3.67 (d, J=7.2 Hz,2H), 1.12 to 1.01 (m, 1H), 0.54-0.48 (m, 2H), 0.28-0.23 (m, 2H); LCMS(method D2): R_(T)=1.33 min, [M+H]⁺=468.

Example 215-(2-Fluoro-4-iodophenylamino)-N-methylimidazo[1,5-a]pyrazine-6-carboxamide

To a solution of5-(2-fluoro-4-iodo-phenylamino)-imidazo[1,5-a]pyrazine-6-carboxylic acidmethyl ester (108 mg, 0.26 mmol) in anhydrous methanol (0.5 mL) wasadded 2M methylamine in THF (1.3 mL, 2.6 mmol, 10 eq), and the reactionmixture was stirred at room temperature under N₂ for 3 days. Thereaction mixture was diluted with ethyl acetate (50 mL). The organiclayer was washed with water and brine, dried (Na₂SO₄), filtered andconcentrated in vacuo. The resultant residue was subjected toreverse-phase preparative HPLC [Gemini-NX (100×30 mm, 10 micron), 0.1%FA in water/acetonitrile, 5-85%, ramp time in 10 minutes, flow at 60ml/min] to afford the title compound as a white solid (48.3 mg, 44.8%).¹H NMR (DMSO-d₆, 400 MHz) δ ppm 10.89 (s, 1H), 8.95 to 8.91 (m, 1H),8.86 (s, 1H), 7.92 (s, 1H), 7.88 (s, 1H), 7.76 (dd, J=8.4 Hz, 1.2 Hz,1H), 7.44 (d, J=6.8 Hz, 1H), 6.51 (t, J=6.8 Hz, 1H), 2.81 (d, 4.0 Hz,3H); LCMS (method E2): R_(T)=12.23 min, [M+H]⁺=412.

Example 225-(4-Bromo-2-fluorophenylamino)-N-(2-hydroxy-ethoxy)imidazo[1,5-a]pyrazine-6-carboxamide

Step 1:5-(4-Bromo-2-fluorophenylamino)-N-(2-(vinyloxy)ethoxy)-imidazo[1,5-a]pyrazine-6-carboxamide

To a stirred solution of5-(4-bromo-2-fluoro-phenylamino)-imidazo[1,5-a]pyrazine-6-carboxylicacid methyl ester (150 mg, 0.41 mmol) andO-(2-vinyloxy-ethyl)hydroxylamine (127 mg, 1.23 mmol, 3.0 eq) inanhydrous THF (7.5 mL) at 0° C. was added lithium hexamethyldisilazide(1M in THF, 1.2 mL, 1.23 mmol, 3.0 eq.), and the reaction mixture wasstirred at room temperature. After 1 h the reaction mixture was quenchedwith saturated aqueous solution of sodium bicarbonate and diluted withethyl acetate. The organic layer was isolated and washed with water andbrine, dried (Na₂SO₄), filtered and concentrated in vacuo. The resultantresidue was subjected to flash chromatography (Si-PPC, gradient 0 to 5%methanol in dichoromethane) to give an oil. Crystallization from DCMether hexane afforded the desired product as a pale orange solid (160.2mg, 89.4%). LCMS (method C): R_(T)=2.53 min, [M+H]⁺=437/439.

Step 2:5-(4-Bromo-2-fluorophenylamino)-N-(2-hydroxy-ethoxy)-imidazo[1,5-a]pyrazine-6-carboxamide

A solution of5-(4-bromo-2-fluorophenylamino)-N-(2-(vinyloxy)ethoxy)-imidazo[1,5-a]pyrazine-6-carboxamide(150 mg, 0.34 mmol) in methanol (4.5 mL) and dichloromethane (8.9 mL)was added 4M HCl in 1,4-dioxane (0.13 mL, 0.5 mmol, 1.5 eq.), and thereaction mixture was stirred at ambient temperature under N₂ for 1 h.Solid sodium carbonate (50 mg) was added to the reaction mixture. Thereaction mixture was absorbed onto silica and then subjected to flashchromatography (Si-PPC, gradient 0% to 15%, methanol in dichloromethane)to afford the title compound as a white solid. (112.1 mg, 79.5%). ¹H NMR(DMSO-d₆, 400 MHz) δ ppm 11.85 (broad s, 1H), 10.32 (broad s, 1H), 8.83(s, 1H), 7.97 (s, 1H), 7.92 (s, 1H), 7.64 (dd, J=10.4 Hz, 2.6 Hz, 1H),7.30 (d, J=8.8 Hz, 1H), 6.77 (t, J=8.8 Hz, 1H), 4.68 (t, J=5.6 Hz, 1H),3.89 (t, 4.8 Hz, 2H), 3.59 (q, J=5.4 Hz, 2H); LCMS (method D1):R_(T)=0.786 min, [M+H]⁺=410/412.

Example 23(S)-5-(4-Bromo-2-fluorophenylamino)-N-(2-hydroxy-propoxy)imidazo[1,5-a]pyrazine-6-carboxamide

Step 1:5-(4-Bromo-2-fluorophenylamino)imidazo[1,5-a]pyrazine-6-carboxylic acid

The desired compound was prepared in an analogous fashion to5-(2-fluoro-4-iodo-phenylamino)-imidazo[1,5-a]pyrazine-6-carboxylicacid, using5-(4-bromo-2-fluoro-phenylamino)-imidazo[1,5-a]pyrazine-6-carboxylicacid methyl ester as the starting material. LCMS (method D1):R_(T)=0.713 min, [M+H]⁺=351/353.

Step 2:(S)-5-(4-Bromo-2-fluorophenylamino)-N-(2-hydroxy-propoxy)imidazo[1,5-a]pyrazine-6-carboxamide

To a solution of5-(4-bromo-2-fluorophenylamino)imidazo[1,5-a]-pyrazine-6-carboxylic acid(100 mg, 0.28 mmol) in anhydrous DMF (1.5 mL) was added, in order,(S)-1-aminooxy-propan-2-ol hydrochloride (37.4 mg, 0.29 mmol, 1.03 eq.),HOBt (40.4 mg, 0.30 mmol, 1.05 eq.), EDCI (57.3 mg, 0.30 mmol, 1.05eq.), and 4-methylmorpholine (0.15 mL, 1.36 mmol, 4.8 eq.). The reactionmixture was stirred at room temperature under N₂ for 7 h and thendiluted with ether (25 mL) and ethyl acetate (25 mL). The organic layerwas washed with water and brine, dried (Na₂SO₄), filtered andconcentrated in vacuo. The resultant residue was subjected to flashchromatography (Si-PPC, gradient 0 to 40% methanol in ethyl acetate) togive an oil. Crystallization from DCM ether hexane afforded the desiredproduct as a white solid (30.3 mg, 25.0%). ¹H NMR (DMSO-d₆, 400 MHz) δppm 11.88 (broad s, 1H), 10.29 (broad s, 1H), 8.82 (s, 1H), 7.98 (s,1H), 7.92 (s, 1H), 7.65 (dd, J=10.6 Hz, 2.2 Hz, 1H), 7.30 (d, J=8.6 Hz,1H), 6.78 (t, J=8.4 Hz, 1H), 4.80 (d, J=4.0 Hz, 1H), 3.90-3.81 (m, 1H),3.75-3.62 (m, 2H), 1.05 (d, J=6.4 Hz, 3H); LCMS (method D2): R_(T)=1.516min, [M+H]⁺=424/426.

Example 24(R)-5-(4-Bromo-2-fluorophenylamino)-N-(2,3-dihydroxy-propoxy)imidazo[1,5-a]pyrazine-6-carboxamide

Step 1:(R)-5-(4-Bromo-2-fluorophenylamino)-N4(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)imidazo[1,5-a]pyrazine-6-carboxamide

The desired compound was prepared in an analogous fashion to5-(4-bromo-2-fluorophenylamino)-N-(2-(vinyloxy)ethoxy)-imidazo[1,5-a]pyrazine-6-carboxamide,using (R)—O((2,2-dimethyl-1,3-dioxolan-4-yl)methyphydroxylamine as thestarting material. LCMS (method D1): R_(T)=0.954 min, [M+H]⁺=480/482.

Step 2:5-(4-Bromo-2-fluorophenylamino)-N-(2-hydroxy-ethoxy)-imidazo[1,5-a]pyrazine-6-carboxamide

The desired compound was prepared in an analogous fashion to5-(4-bromo-2-fluorophenylamino)-N-(2-hydroxy-ethoxy)-imidazo[1,5-c]pyrazine-6-carboxamide,using(R)-5-(4-bromo-2-fluorophenylamino)-N-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)imidazo[1,5-a]pyrazine-6-carboxamideas the starting material. ¹H NMR (DMSO-d₆, 400 MHz) δ ppm 11.90 (broads, 1H), 10.38 (broad s, 1H), 8.81 (s, 1H), 7.96 (s, 1H), 7.91 (s, 1H),7.65 (d, J=10.4 Hz, 1H), 7.30 (d, J=8.4 Hz, 1H), 6.77 (t, J=8.8 Hz, 1H),4.87 (s, 1H), 4.56 (broad s, 1H), 3.93 (dd, J=9.6 Hz, 3.2 Hz, 1H),3.79-3.69 (m, 2H), 3.43-3.35 (m, 2H); LCMS (method D1): R_(T)=0.724 min,[M+H]⁺=440/442.

Example 255-(4-Bromo-2-fluorophenylamino)-N-(cyclopropyl-methoxy)imidazo[1,5-a]pyrazine-6-carboxamide

The title compound was prepared in an analogous fashion toN-(cyclopropylmethoxy)-5-(2-fluoro-4-iodophenylamino)imidazo[1,5-a]pyrazine-6-carboxamide,using5-(4-bromo-2-fluoro-phenylamino)-imidazo[1,5-a]pyrazine-6-carboxylicacid methyl ester as the starting material. ¹H NMR (MeOD, 400 MHz) δ ppm8.74 (s, 1H), 7.87 (s, 1H), 7.84 (s, 1H), 7.48 (dd, J=10.4 Hz, 3.2 Hz,1H), 7.30 (d, 8.4 Hz, 1H), 6.75 (t, J=8.4 Hz, 1H), 3.79 (d, J=7.2 Hz,2H), 1.26-1.13 (m, 1H), 0.62-0.55 (m, 2H), 0.36 to 0.30 (m, 2H); LCMS(method D1): R_(T)=0.985 min, [M+H]⁺=420/422.

I claim:
 1. A compound5-(2-fluoro-4-iodophenylamino)-imidazo[1,5-a]pyridine-6-carboxylicacid(2-hydroxyethoxy)-amide, or a pharmaceutically acceptable saltthereof.
 2. The compound of claim 1 where the compound is a free base.